Androgen receptor modulators and methods of use thereof

ABSTRACT

Compounds of structural formula (I) as herein defined are disclosed as useful in a method for modulating the androgen receptor in a tissue selective manner in a patient in need of such modulation, as well as in a method of agonizing the androgen receptor in a patient, and in particular the method wherein the androgen receptor is antagonized in the prostate of a male patient or in the uterus of a female patient and agonized in bone and/or muscle tissue. These compounds are useful in the treatment of conditions caused by androgen deficiency or which can be ameliorated by androgen administration, including: osteoporosis, periodontal disease, bone fracture, bone damage following bone reconstructive surgery, sarcopenia, frailty, aging skin, male hypogonadism, post-menopausal symptoms in women, female sexual dysfunction, atherosclerosis, hypercholesterolemia, hyperlipidemia, aplastic anemia and other hematopoietic disorders, pancreatic cancer, renal cancer, arthritis and joint repair, alone or in combination with other active agents. In addition, these compounds are useful as pharmaceutical composition ingredients alone and in combination with other active agents.

This application is a §371 National Stage application ofPCT/US2004/013787, filed on May 3, 2004, which claims priority from:U.S. Provisional Application No. 60/468,579 filed May 7, 2003.

CROSS-REFERENCE TO RELATED APPLICATIONS

Not applicable.

BACKGROUND OF THE INVENTION

Androgens play important roles in post-natal development that are mostpronounced at adrenarche and pubarche. Androgen production promotes themusculoskeletal anabolism associated with the pubertal growth in bothmales and females. At puberty, ovarian and testicular androgens areresponsible for pubertal hair, acne, and enhancement of libido. Inmales, exposure to 100-fold increased levels of endogenous androgensresults in the gender dimorphism in bone mass, muscle mass (positivenitrogen balance), and upper body strength, and are required for normalsexual development (genitalia, spermatogenesis, prostate and seminalvesicle maturation). Delay in puberty decreases the peak bone massachieved during adulthood. (Bhasin, S., et al., Eds. Pharmacology,Biology, and Clinical Applications of Androgens: Current Status andFuture Prospects. Wiley-Liss, Inc.: New York, 1996). In women, naturalmenopause causes virtually complete loss of ovarian estrogen productionand gradually reduces ovarian production of androgen by approximately50%. The physiological consequences of reduced androgen production aftermenopause are evident in decreased energy and libido, and contributesignificantly in many women to vasomotor symptoms. Decreased androgenoutput is also thought to contribute—along with declining pituitarygrowth hormone (GH) secretion and insulin derived growth factor 1 (IGF1)action—to age-dependent sarcopenia, negative nitrogen balance and lossof bone mass. (Vestergaard, et al., Effect of sex hormone replacement onthe insulin-like growth factor system and bone mineral: across-sectional and longitudinal study in 595 perimenopausal womenparticipating in the Danish Osteoporosis Prevention Study, J ClinEndocrinol Metab. 84:2286-90, 1999; and Bhasin, et al., Eds.Pharmacology, Biology, and Clinical Applications of Androgens: CurrentStatus and Future Prospects, Wiley-Liss, Inc.: New York. 1996).Postmenopausal osteoporosis results mainly from estrogen deficiency.However, many women who received estrogen replacement therapy still losebone with age and develop age-related osteoporotic fractures (albeit ata lower rate than those taking estrogens), indicating that bothestrogens and androgens play important roles for bone health in bothwomen and men. The simultaneous decreases in bone mass, muscle mass andmuscle strength increase the risk of falls and especially of hipfractures in both men and women>65 years of age. In fact, one-third ofall hip fractures occur in men.

The androgen receptor (AR) belongs to the nuclear receptor superfamilyand controls transcription in a ligand dependent manner (Brinklan, etal., Mechanisms of androgen receptor activation and function, J. Ster.Biochem. Mol. Biol. 69, 307-313, 1999). Upon androgen binding, AR bindsdirectly to specific DNA sequences present in the promoter region ofandrogen responsive genes, termed androgen response elements (AREs), tostimulate transcription. Using ARE-dependent transcription as acriterion, agents that bind to AR and stimulate ARE-dependenttranscription can be classified as agonists, and those that bind to ARand suppress ARE-dependent transcription are classified as antagonists.A number of natural or synthetic androgen agonists have been used fortreatment of musculoskeletal or hematopoietic disorders and for hormonereplacement therapy. In addition, AR antagonists, such as flutamide orbicalutamide, are used for treatment of prostate cancer. However,clinical use of these androgen agonists or antagonists have been limitedbecause of undesirable effects, such as hirsutism and prostateenlargement for agonists, and bone loss, fracture, gynecomastia andsarcopenia for antagonists. It would be useful to have availableandrogens with tissue selective agonistic activity, which increase boneformation and muscle mass but do not induce the virilization.

Osteoporosis is characterized by bone loss, resulting from an imbalancebetween bone resorption (destruction) and bone formation, which startsin the fourth decade continues throughout life at the rate of about 1-4%per year (Eastell, Treatment of postmenopausal osteoporosis, New Eng. J.Med. 338: 736, 1998). In the United States, there are currently about 20million people with detectable fractures of the vertebrae due toosteoporosis. In addition, there are about 250,000 hip fractures peryear due to osteoporosis, associated with a 12%-20% mortality ratewithin the first two years, while 30% of patients require nursing homecare after the fracture and many never become fully ambulatory again. Inpostmenopausal women, estrogen deficiency leads to increased boneresorption resulting in bone loss in the vertebrae of around 5% peryear, immediately following menopause. Thus, first linetreatment/prevention of this condition is inhibition of bone resorptionby bisphosphonates, estrogens, selective estrogen receptor modulators(SERMs) and calcitonin. However, inhibitors of bone resorption are notsufficient to restore bone mass for patients who have already lost asignificant amount of bone. The increase in spinal BMD attained bybisphosphonate treatment can reach 11% after 7 years of treatment withalendronate. In addition, as the rate of bone turnover differs from siteto site; higher in the trabecular bone of the vertebrae than in thecortex of the long bones, the bone resorption inhibitors are lesseffective in increasing hip BMD and preventing hip fracture. Therefore,osteoanabolic agents, which increase cortical/periosteal bone formationand bone mass of long bones, would address an unmet need in thetreatment of osteoporosis especially for patients with high risk of hipfractures. The osteoanabolic agents also complement the bone resorptioninhibitors that target the trabecular envelope, leading to abiomechanically favorable bone structure. (Schmidt, et al., Anabolicsteroid: Steroid effects on bone in women, 1996, In: J. P. Bilezikian,et al., Ed. Principles of Bone Biology. San Diego: Academic Press.)

A number of studies provide the proof of principle that androgens areosteoanabolic in women and men. Anabolic steroids, such as nandrolonedecanoate or stanozolol, have been shown to increase bone mass inpostmenopausal women. Beneficial effects of androgens on bone inpost-menopausal osteoporosis are well documented in recent studies usingcombined testosterone and estrogen administration (Hofbauer, et al.,Androgen effects on bone metabolism: recent progress and controversies,Eur. J. Endocrinol. 140, 271-286, 1999). Combined treatment increasedsignificantly the rate and extent of the rise in BMD (lumbar and hip),relative to treatment with estrogen alone. Additionally,estrogen-progestin combinations that incorporate an androgenic progestin(norethindrone) rather than medroxyprogesterone acetate yielded greaterimprovements in hip BMD. These results have recently been confirmed in alarger (N=311) 2 year, double blind comparison study in which oralconjugated estrogen (CEE) and methyltestosterone combinations weredemonstrated to be effective in promoting accrual of bone mass in thespine and hip, while conjugated estrogen therapy alone prevented boneloss (A two-year, double-blind comparison of estrogen-androgen andconjugated estrogens in surgically menopausal women: Effects on bonemineral density, symptoms and lipid profiles. J Reprod Med.44(12):1012-20, 1999). Despite the beneficial effects of androgens inpostmenopausal women, the use of androgens has been limited because ofthe undesirable virilizing and metabolic action of androgens. The datafrom Watts and colleagues demonstrate that hot flushes decrease in womentreated with CEE+methyltestosterone; however, 30% of these womensuffered from significant increases in acne and facial hair, acomplication of all current androgen pharmacotherapies (Watts, et al.,Comparison of oral estrogens and estrogens plus androgen on bone mineraldensity, menopausal symptoms, and lipid-lipoprotein profiles in surgicalmenopause, Obstet. Gynecol. 85, 529-537, 1995). Moreover, the additionof methyltestosterone to CEE markedly decreased HDL levels, as seen inother studies. Thus, the current virilizing and metabolic side effectprofile of androgen therapies provide a strong rationale for developingtissue selective androgen agonists for bone.

It is well established that androgens play an important role in bonemetabolism in men, which parallels the role of estrogens in women.(Anderson, et al., Androgen supplementation in eugonadal men withosteoporosis—effects of 6 months of treatment on bone mineral densityand cardiovascular risk factors, Bone 18: 171-177, 1996). Even ineugonadal men with established osteoporosis, the therapeutic response totestosterone treatment provides additional evidence that androgens exertimportant osteoanabolic effects. Mean lumbar BMD increased from 0.799gm/cm² to 0.839 g/cm², in 5 to 6 months in response to 250 mg oftestosterone ester IM q fortnight (p=0.001). A common scenario forandrogen deficiency occurs in men with stage D prostate cancer(metastatic) who undergo androgen deprivation therapy (ADT). Endocrineorchiectomy is achieved by long acting GnRH agonists, while androgenreceptor blockade is implemented with flutamide or bicalutamide (ARantagonists). In response to hormonal deprivation, these men suffer fromhot flushes, significant bone loss, weakness, and fatigue. In a recentpilot study of men with stage D prostate cancer, osteopenia (50% vs.38%) and osteoporosis (38% vs. 25%) were more common in men who hadundergone ADT for>1 yr than the patients who did not undergo ADT (Wei,et al. Androgen deprivation therapy for prostate cancer results insignificant loss of bone density, Urology 54: 607-11, 1999). Lumbarspine BMD was significantly lower in men who had undergone ADT(P=0.008). Thus, in addition to the use of tissue selective AR agonistsfor osteoporosis, tissue selective AR antagonists in the prostate thatlack antagonistic action in bone and muscle may be a useful treatmentfor prostate cancer, either alone or as an adjunct to traditional ADTsuch as GnRH agonist/antagonist.

Additionally, it has been re ported that patients with pancreatic cancertreated with the antiandrogen flutamide have been found to haveincreased survival time. (Greenway, B. A., Drugs & Aging, 17(3), 161,2000). The tissue selective androgen receptor modulators of the presentinvention may be employed for treatment of pancreatic cancer, eitheralone or as an adjunct to treatment with an antiandrogen.

The possibility of tissue selective AR agonism was suggested by androgeninsensitivity syndrome (AIS), which results from mutations in AR genelocated at X chromosome. (Quigley, et al., Androgen receptor defects:Historical, clinical, and molecular perspectives. Endocrine Reviews. 16:546-546, 1995). These mutations cause different degrees of androgeninsensitivity. While complete lack of androgen responsiveness developsas a female phenotype with female-type bones, subtle mutations (oneamino acid substitution) of AR may lead to partial AIS with differentdegrees of abnormality in male sexual development often with male-typeskeleton. A similar aberration in male sex organ development is alsofound in individuals with mutations in 5α-reductase type 2 gene, thatconverts testosterone to 5α-dihydro-testosterone (5α-DHT) (Mendonca, etal., Male pseudohermaphroditism due to steroid 5alpha-reductase 2deficiency: Diagnosis, psychological evaluation, and management,Medicine (Baltimore), 75 :64-76 (1996)). These patients exhibit partialdevelopment of male organs with normal male skeleton, indicating thattestosterone cannot substitute for 5α-DHT as an activator of AR ingenital development. This ligand specificity for certain tissues raisesthe possibility that androgenic compounds with AR agonistic activitycould have specificity for certain tissues, such as bone, while lackingactivity in other tissues, such as those responsible for virilization.

Recent advances in the steroid hormone receptor field uncovered thecomplex nature of transcription controlled by AR and other nuclearreceptors (Brinkman, et al., Mechanisms of androgen receptor activationand function, J. Ster. Biochem. Mol. Biol. 69, 307-313 1999). Uponbinding to ARE as a homo-dimer, agonist-bound AR stimulatestranscription by recruiting a large enzymatic co-activator complex thatincludes GRIP1/TIF2, CBP/p300 and other coactivators. Transcriptionalactivities of AR have been functionally mapped to both the N-terminaldomain (NTD) and C-terminal ligand binding domain (LBD), also termedactivation function AF1 and AF2, respectively. A feature of AR is theligand mediated interaction of AR NTD with LBD (N-C interaction) whichis essential for most ligand induced transcriptional activation. Inaddition, agonist-bound AR can also suppress transcription viaprotein-protein interaction with transcription factor complexes such asAP1, NFκB and Ets family. Both AR agonist-induced transcriptionalactivation and repression are context (cell type and promoter) dependentand are reversed by AR antagonists, providing the possibility forligand-dependent, context specific agonism/antagonism. Androgenicligands, thus, may lead to tissue selective AR agonism or partial ARagonism/antagonism, and have been named selective AR modulators (SARMs).

What is needed in the art are compounds that can produce the samepositive responses as androgen replacement therapy without the undesiredside effects. Also needed are androgenic compounds that exert selectiveeffects on different tissues of the body. In this invention, wedeveloped a method to identify SARMs using a series of in vitrocell-assays that profiles ligand mediated activation of AR, such as (i)N-C interaction, (ii) transcriptional repression, (iii) transcriptionalactivation dependent on AF1 or AF2 or native form of AR. SARM compoundsin this invention, identified with the methods listed above, exhibittissue selective AR agonism in vivo, i. e. agonism in bone (stimulationof bone formation in rodent model of osteoporosis) and antagonism inprostate (minimal effects on prostate growth in castrated rodents andantagonism of prostate growth induced by AR agonists). Such compoundsare ideal for treatment of osteoporosis in women and men as amonotherapy or in combination with inhibitors of bone resorption, suchas bisphosphonates, estrogens, SERMs, cathepsin K inhibitors, αVβ3antagonists, calcitonin, proton pump inhibitors. SARM compounds may alsobe employed for treatment of prostate disease, such as prostate cancerand benign prostate hyperplasia (BPH). Moreover, compounds in thisinvention exhibit minimal effects on skin (acne and facial hair growth)and can be used for treatment of hirsutism. Additionally, compounds inthis invention can exhibit muscle growth and can be used for treatmentof sarcopenia and frailty. Moreover, compounds in this invention canexhibit androgen agonism in the central nervous system and can be usedto treat vasomotor symptoms (hot flush) and can increase energy andlibido, particularly in post-menopausal women. The compounds of thepresent invention may be used in the treatment of prostate cancer,either alone or as an adjunct to traditional GnRH agonist/antagonisttherapy for their ability to restore bone, or as a replacement forantiandrogen therapy because of the ability to antagonize androgen inthe prostate, and minimize bone depletion in the skeletal system.Further, the compounds of the present invention may be used for theirability to restore bone in the treatment of pancreatic cancer as anadjunct to treatment with antiandrogen, or as solo agents for theirantiandrogenic properties, offering the advantage over traditionalantiandrogens of being bone-sparing. Additionally, compounds in thisinvention can increase the number of blood cells, such as red bloodcells and platelets and can be used for treatment of hematopoieticdisorders such as aplastic anemia. Finally, compounds in this inventionhave minimal effects on lipid metabolism, thus considering their tissueselective androgen agonism listed above, the compounds in this inventionare ideal for hormone replacement therapy in hypogonadic (androgendeficient) men.

U.S. Pat. No. 5,696,130; U.S. Pat. No. 5,688,808; U.S. Pat. No.6,093,821; and WO 01/16139 disclose nonsteroidal steroid receptormodulating compounds.

WO 03/026568; WO 03/26568; WO 03/011302 and U.S. 2003/0065004 disclosesandrostane derivatives as androgen receptor modulators.

16- or 17β-substituted androstane derivatives are disclosed in thefollowing: U.S. Pat. No. 4,220,775; U.S. Pat. No. 4,377,584 U.S. Pat.Nos. 5,084,574; 5,116,983; U.S. Pat. No. 5,237,064; U.S. Pat. No.5,438,061; U.S. Pat. No. 5,620,986; U.S. Pat. No. 5,639,741; U.S. Pat.No. 5,693,809; U.S. Pat. No. 5,693,810; U.S. Pat. No. 5,696,266; U.S.Pat. No. 5,710,275; U.S. Pat. No. 5,777,134; U.S. Pat. No. 5,817,802;U.S. Pat. No. 5,994,362; US2001/0001099A1; WO 92/16213; WO 93/23038; WO93/23039; WO 93/23048; WO 93/23053; WO 94/07909; WO 94/20104; WO95/00531; WO 95/00532; WO 97/30069, EP 0 572 166; Solomons, et al.,“Synthesis and antimicrobial properties of 17β-amino-4-aza-5α-androstaneand derivatives”, J. Pharm. Sci. 63(1): 19 (1974); Rasmusson, et al.“Azasteroids as Inhibitors of Rat Prostatic 5α-Reductase”, J. Med. Chem.27: 1690 (1984); Rasmusson, et al., “Azasteroids: Structure-ActivityRelationships for Inhibition of 5α-Reductase and of Androgen ReceptorBinding” J. Med. Chem. 29(11): 2298 (1986); Li et al., “Synthesis and inVitro Activity of 17β-(N-Alkyl/arylformamido andN-alkyl/arylalkyl/arylamido)-4-methyl-4-aza-3-oxo-5a-androstan-3-ones asInhibitors of Human 5a-Reductases and Antagonists of the AndrogenReceptor” J. Med. Chem. 38(7): 1158 (1995); Lourdusamy et al.,“Synthesis and in vitro study of17β-[N-ureylene-N,N′-disubstituted]4-methyl-4-aza-5α-androstan-3-ones asselective inhibitors of type I 5α-reductase” Bioorg. Med. Chem. 5(2):305 (1997); Chen et al., “Activity of 17β-(N-alkyl/arylformamido) and17B-[N-alkyl/aryl)alkyl/arylamido]-4-methyl-4-aza-5a-androstan-3-ones as5α-reductase inhibitors in the hamster flank organ and ear” Can. J.Invest. Dermatol. 111(2): 273 (1998).

Tolman, et al.,“4-Methyl-3-oxo-4-aza-5α-androst-1-ene-17β-N-aryl-carboxamides: AnApproach to Combined Androgen Blockade 5α-Reductase Inhibition withAndrogen Receptor Binding In Vitro”, J. Steroid Biochem. Molec. Biol.60(5-6): 303 (1997), discloses that 4-N-methyl substitution andunsaturation of the A ring at the 1-2 position of 4-aza-5α-androstan-3-one 17β-carboxamide 5α-reductase type 2 inhibitorsincreased androgen receptor affinity and that N-aryl substitution at the17-carboxamide increased affinity for the type 1 isozyme of5α-reductase. Tolman, et al., posit that these compounds will haveutility in the treatment of prostatic carcinoma and will providecomplete androgen blockade.

U.S. Pat. No. 5,945,412; WO 98/25623 and WO 98/25622 are directed to theuse of 5α-reductase inhibitors, including16-substituted-5α-androstan-3-ones, finasteride and17-alkyl-4-aza-5α-androstan-3-ones, respectively, as anti-resorptiveagents useful in the prevention and treatment of bone loss, as well asprevention and treatment of osteoporosis and osteopenia and otherdiseases where inhibiting bone loss may be beneficial, including:Paget's disease, malignant hypercalcemia, periodontal disease, jointloosening and metastatic bone disease, as well as reducing the risk offractures, both vertebral and nonvertebral. In the treatment ofosteoporosis, the activity of bone resorption inhibitors is distinctfrom the activity of tissue selective androgen receptor modulators(SARMs). Rather than inhibiting bone resorption, the SARMs of thepresent invention stimulate bone formation, acting preferentially oncortical bone, which is responsible for a significant part of bonestrength. Bone resorption inhibitors, in contrast, act preferentially ontrabecular bone.

SUMMARY OF THE INVENTION

Compounds of structural formula (I) as herein defined are disclosed asuseful in a method for modulating the androgen receptor in a tissueselective manner in a patient in need of such modulation, as well as ina method of agonizing the androgen receptor in a patient, and inparticular the method wherein the androgen receptor is agonized in boneand/or muscle tissue and antagonized in the prostate of a male patientor in the uterus of a female patient. These compounds are useful in thetreatment of conditions caused by androgen deficiency or which can beameliorated by androgen administration, including: osteoporosis,periodontal disease, bone fracture, bone damage following bonereconstructive surgery, sarcopenia, frailty, aging skin, malehypogonadism, post-menopausal symptoms in women, female sexualdysfunction, atherosclerosis, hypercholesterolemia, hyperlipidemia,aplastic anemia and other hematopoietic disorders, pancreatic cancer,renal cancer, arthritis and joint repair, alone or in combination withother active agents. In addition, these compounds are useful aspharmaceutical composition ingredients alone and in combination withother active agents.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to compounds useful as tissue selectiveandrogen receptor modulators (SARMs).

Compounds of the present invention, which may be prepared in accordancewith the methods described herein, have been found to be tissueselective modulators of the androgen receptor (SARMs). In one aspect,compounds of the present invention may be useful to agonize the androgenreceptor in a patient, and in particular to agonize the androgenreceptor in bone and/or muscle tissue and antagonize the androgenreceptor in the prostate of a male patient or in the uterus of a femalepatient and agonize the androgen receptor in bone and/or muscle tissue.In another aspect of the present invention, compounds of structuralformula I may be useful to agonize the androgen receptor in bone and/ormuscle tissue and antagonize the androgen receptor in the prostate of amale patient or in the uterus or skin of a female patient. The agonismin bone can be assayed through stimulation of bone formation in therodent model of osteoporosis, and the antagonism in the prostate can beassayed through observation of minimal effects on prostate growth incastrated rodents and antagonism of prostate growth induced by ARagonists, as detailed in the Examples.

Yet another aspect of the present invention is a method to identifySARMs using a series of in vitro cell-based assays. In the first ofthese series of assays (which may in practice be performed in anyorder), agonists of the androgen receptor (AR) are characterized bymeasuring Rhesus AR-dependent suppression of the human MMP-1 promoter inBEP G-2 cells transiently transfected with MMP1/luciferase promoter andthe Rhesus AR (RhAR). (Schneikert, et al., Androgen receptor-Ets proteininteraction is a novel mechanism for steroid hormone-mediateddown-modulation of matrix metalloproteinase expression, J Biol Chem.September 27:271(39):23907-13, 1996. In this instance, the Rhesus ARmediates ligand-dependent promoter suppression of the MMP1 promoter viaprotein-protein interactions with uncharacterized factors bound to theEts cognate. SARMs display agonist activity in this assay by repressingtranscription. A compound's in vivo viralizing potential, mediatedthrough the AR, is reflected in vitro by its ability to stably assemblean AR N-terminal/C-terminal interaction. (He, et al., Activationfunction in the human androgen receptor ligand binding domain mediatesinterdomain communication with the NH(2)-terminal domain. J Biol Chem.274: 37219 1999). Two transcription assays have been developed to screenfor compounds with reduced potential to induce virilizing effects invivo. In the first transcription assay, the in vivo virilizing potentialmediated by activated androgen receptors is reflected in the capacity ofrhAR ligands to induce the N-terminal/C-terminal interaction in amammalian 2-hybrid assay in CV-1 monkey kidney cells. SARMs display weakor no agonist activity in this assay. In the second transcription assay,the same test compound is assayed in the same format in the presence ofa full virilizing androgen agonist and the capacity of the compound toantagonize the stimulation induced by the full androgen agonist isquantified. SARMs of the present invention display antagonist activityin in this assay.

In a further aspect of the present invention are compounds of structuralformula I that antagonize the androgen receptor in the prostate of amale patient or in the uterus of a female patient, but not inhair-growing skin or vocal cords, and agonize the androgen receptor inbone and/or muscle tissue, but not in organs which control blood lipidlevels (e.g. liver). These compounds are useful in the treatment ofconditions caused by androgen deficiency or which can be ameliorated byandrogen administration, including: osteoporosis, osteopenia,glucocorticoid-induced osteoporosis, periodontal disease, HIV-wasting,cancer cachexia, bone fracture, bone damage following bonereconstructive surgery, muscular dystrophies, sarcopenia, frailty, agingskin, male hypogonadism, post-menopausal symptoms in women, femalesexual dysfunction, premature ovarian failure, autoimmune disease,atherosclerosis, hypercholesterolemia, hyperlipidemia, aplastic anemiaand other hematopoietic disorders, arthritis and joint repair, alone orin combination with other active agents. Still further, the compounds ofthe present invention are useful in treating insulin resistence,including NIDDM, obesity and growth retardation associated with obesity,hyperinsulinemia, as well as Metabolic Syndrome, or “Syndrome X” asdefined in Johannsson, J. Clin Endocrin. Metabl 82: 727-34 (1997). Inaddition, these compounds are useful as pharmaceutical compositioningredients alone and in combination with other active agents.

The compounds of the present invention may be used to treat conditionswhich are caused by androgen deficiency or which can be ameliorated byandrogen administration, including, but not limited to: osteoporosis,osteopenia, glucocorticoid-induced osteoporosis, periodontal disease,HIV-wasting, cancer cachexia, bone fracture, bone damage following bonereconstructive surgery, muscular dystrophies, sarcopenia, frailty, agingskin, male hypogonadism, post-menopausal symptoms in women, femalesexual dysfunction, premature ovarian failure, autoimmune disease,atherosclerosis, hypercholesterolemia, hyperlipidemia, aplastic anemiaand other hematopoietic disorders, arthritis and joint repair, alone orin combination with other active agents. The compounds can also beemployed to increase lean body mass and reduce the risk of insulinresistance and diabetes as well as to treat insulin resistence,including NIDDM, obesity and growth retardation associated with obesity,hyperinsulinemia, as well as Metabolic Syndrome, or “Syndrome X” asdefined in Johannsson, J. Clin Endocrin. Metabl 82: 727-34 (1997).Treatment is effected by administration of a therapeutically effectiveamount of the compound of structural formula I to the patient in need ofsuch treatment.

The compounds of structural formula I may also be employed as adjunctsto traditional androgen depletion therapy in the treatment of prostatecancer to restore bone, minimize bone loss, and maintain bone mineraldensity. In this manner, they may be employed together with traditionalandrogen deprivation therapy, including GnRH agonists/antagonists suchas leuprolide. It is also possible that the compounds of structuralformula I may be used in combination with antiandrogens such asflutamide, hydroxy-flutamide (the active form of flutamide), andCasodex™ (the trademark for ICI 176,334 from Imperial ChemicalIndustries PLC, presently Astra-Zeneca) in the treatment of prostatecancer.

Further, the compounds of the present invention may also be employed inthe treatment of pancreatic cancer, either for their androgen antagonistproperties or as an adjunct to an antiandrogen such as flutamide,hydroxy-flutamide (the active form of flutamide), and Casodex™ (thetrademark for ICI 176,334).

Compounds of structural formula I have minimal negative effects on lipidmetabolism, thus considering their tissue selective androgen agonismlisted above, the compounds in this invention are ideal for hormonereplacement therapy in hypogonadic (androgen deficient) men.

Additionally, compounds in this invention can increase the number ofblood cells, such as red blood cells and platelets and can be used fortreatment of hematopoietic disorders such as aplastic anemia.

Compounds of the present invention are described by the followingchemical formula I:

wherein:

-   “a” and “b” are independently selected from a single bond and a    double bond;-   X is selected from:    -   (1) —C(O)—,    -   (2) —C(O)—O—,    -   (3) —C(O)—N(R⁷)—, and    -   (4) —S(O)_(n)—;-   R¹ is selected from:    -   (1) C₁₋₃ alkyl,    -   (2) C₂₋₃ alkenyl,    -   (3) C₃₋₆ cycloalkyl,    -   (4) C₁₋₃ alkyl wherein one or more of the hydrogen atoms has        been replaced with a fluorine atom,    -   (5) aryl, and    -   (6) aryl-C₁₋₃ alkyl;-   R² is selected from:    -   (1) aryl, either unsubstituted or substituted,    -   (2) C₁₋₈ alkyl, unsubstituted or substituted,    -   (3) perfluoroC₁₋₈ alkyl,    -   (4) aryl-C₁₋₆ alkyl-,    -   (5) C₂₋₈ alkenyl, unsubstituted or substituted,    -   (6) aryl-C₂₋₈ alkenyl, unsubstituted or substituted,    -   (7) C₃₋₈ cycloalkyl, either unsubstituted or substituted, and    -   (8) cycloheteroalkyl, unsubstituted or substituted;-   R³ is selected from H, perfluoro C₁₋₈ alkyl, and C₁₋₈ alkyl,    unsubstituted or substituted with one to three halogen atoms, or R²    and R³, together with the nitrogen atom, and the “X” moiety to which    they are attached, form a 5- to 7-membered heterocyclic ring,    optionally containing one or two additional heteroatoms selected    from N, S, and O, optionally having one or more degrees of    unsaturation, optionally fused to a 6-membered heteroaromatic or    aromatic ring, either unsubstituted or substituted;-   R⁴ and R⁵ are each independently selected from    -   (1) hydrogen,    -   (2) halogen,    -   (3) aryl,    -   (4) C₁₋₈ alkyl,    -   (5) C₃₋₈ cycloalkyl,    -   (6) C₃₋₈ cycloheteroalkyl,    -   (7) aryl C₁₋₆alkyl,    -   (8) amino C₀₋₆alkyl,    -   (9) C₁₋₆ alkylamino C₁₋₆alkyl,    -   (10) (C₁₋₆ alkyl)₂amino C₀₋₆alkyl,    -   (11) aryl C₀₋₆ alkylamino C₀₋₆alkyl,    -   (12) (aryl C₀₋₆ alkyl)₂amino C₀₋₆alkyl,    -   (13) C₁₋₆ alkylthio,    -   (14) aryl C₀₋₆alkylthio,    -   (15) C₁₋₆ alkylsulfinyl,    -   (16) aryl C₀₋₆alkylsulfinyl,    -   (17) C₁₋₆ alkylsulfonyl,    -   (18) aryl C₀₋₆alkylsulfonyl,    -   (19) C₁₋₆ alkoxy C₀₋₆alkyl,    -   (20) aryl C₀₋₆ alkoxy C₀₋₆alkyl,    -   (21) hydroxycarbonyl C₀₋₆alkyl,    -   (22) C₁₋₆ alkoxycarbonyl C₀₋₆alkyl,    -   (23) aryl C₀₋₆ alkoxycarbonyl C₀₋₆alkyl,    -   (24) hydroxycarbonyl C₁₋₆ alkyloxy,    -   (25) hydroxy C₀₋₆alkyl,    -   (26) cyano,    -   (27) nitro,    -   (28) perfluoroC₁₋₄alkyl,    -   (29) perfluoroC₁₋₄alkoxy,    -   (30) C₀₋₆ alkylcarbonyl,    -   (31) C₁₋₆ alkylcarbonyloxy,    -   (32) aryl C₀₋₆alkylcarbonyloxy,    -   (33) C₁₋₆ alkylcarbonylamino,    -   (34) aryl C₀₋₆ alkylcarbonylamino,    -   (35) C₁₋₆ alkylsulfonylamino,    -   (36) aryl C₀₋₆alkylsulfonylamino,    -   (37) C₁₋₆ alkoxycarbonylamino,    -   (38) aryl C₀₋₆ alkoxycarbonylamino,    -   (39) C₁₋₆alkylaminocarbonylamino,    -   (40) aryl C₀₋₆alkylaminocarbonylamino,    -   (41) (C₁₋₆alkyl)₂ aminocarbonylamino,    -   (42) (aryl C₀₋₆alkyl)₂ aminocarbonylamino,    -   (43) (C₁₋₆alkyl)₂ aminocarbonyloxy,    -   (44) (aryl C₀₋₆alkyl)₂ aminocarbonyloxy, and    -   (45) spiro-C₃₋₈cycloalkyl;    -   or, R⁴ and R⁵ together form an oxo group or ═CH—R⁶ or a spiro        C₃₋₇ cycloalkyl ring, substituted with R⁶;-   R⁶ is selected from:    -   (1) hydrogen, and    -   (2) C₁₋₄ alkyl;-   R⁷ is selected from H, perfluoro C₁₋₈ alkyl, and C₁₋₈ alkyl,    unsubstituted or substituted with one to three halogen atoms;-   n is selected from: 0, 1, and 2;-   or a pharmaceutically acceptable salt thereof.

In one embodiment of the present invention, “b” is a single bond. In oneclass of this embodiment, “b” is a single bond, and “a” is a doublebond. In another class of this embodiment, “b” is a single bond, and “a”is a single bond.

In another embodiment of the present invention, “b” is a double bond. Inone class of this embodiment, “b” is a double bond, and “a” is a doublebond. In another class of this embodiment, “b” is a double bond, and “a”is a single bond.

In one embodiment of the present invention, R¹ is selected from:

-   -   (1) C₁₋₃ alkyl,    -   (2) C₂₋₃ alkenyl,    -   (3) C₃₋₆ cycloalkyl,    -   (4) trifluoromethyl,    -   (5) phenyl,    -   (6) phenyl-C₁₋₃ alkyl.

In another embodiment of the present invention R¹ is selected from:

-   -   (1) C₁₋₃ alkyl,    -   (2) C₂₋₃ alkenyl,    -   (3) C₃₋₆ cycloalkyl, and    -   (4) trifluoromethyl.

In still another embodiment of the present invention R¹ is selectedfrom:

-   -   (1) C₁₋₂ alkyl,    -   (2) C₃₋₆ cycloalkyl, and    -   (3) trifluoromethyl.

In yet another embodiment of the present invention R¹ is selected from:

-   -   (1) methyl,    -   (2) cyclopropyl, and    -   (3) trifluoromethyl.

In one class of this embodiment, R¹ is selected from methyl andcyclopropyl. In a subclass of this embodiment R¹ is methyl.

In one embodiment of the present invention, R² is aryl, eitherunsubstituted or substituted with one to three substituents selectedfrom:

-   -   (1) halogen,    -   (2) aryl,    -   (3) C₁₋₈ alkyl,    -   (4) C₃₋₈ cycloalkyl,    -   (5) C₃₋₈ cycloheteroalkyl,    -   (6) aryl C₁₋₆alkyl,    -   (7) amino C₀₋₆alkyl,    -   (8) C₁₋₆ alkylamino C₀₋₆alkyl,    -   (9) (C₁₋₆ alkyl)₂amino C₀₋₆alkyl,    -   (10) aryl C₀₋₆ alkylamino C₀₋₆alkyl,    -   (11) (aryl C₀₋₆ alkyl)₂amino C₀₋₆alkyl,    -   (12) C₁₋₆ alkylthio,    -   (13) aryl C₀₋₆alkylthio,    -   (14) C₁₋₆ alkylsulfinyl,    -   (15) aryl C₀₋₆alkylsulfinyl,    -   (16) C₁₋₆ alkylsulfonyl,    -   (17) aryl C₀₋₆alkylsulfonyl,    -   (18) C₁₋₆ alkoxy C₀₋₆alkyl,    -   (19) aryl C₀₋₆ alkoxy C₀₋₆alkyl,    -   (20) hydroxycarbonyl C₀₋₆alkyl,    -   (21) C₁₋₆ alkoxycarbonyl C₀₋₆alkyl,    -   (22) aryl C₀₋₆ alkoxycarbonyl C₀₋₆alkyl,    -   (23) hydroxycarbonyl C₁₋₆ alkyloxy,    -   (24) hydroxy C₀₋₆alkyl,    -   (25) cyano,    -   (26) nitro,    -   (27) perfluoroC₁₋₄alkyl,    -   (28) perfluoroC₁₋₄alkoxy,    -   (29) C₁₋₆ alkylcarbonyloxy,    -   (30) aryl C₀₋₆alkylcarbonyloxy,    -   (31) alkyl C₁₋₆ carbonylamino,    -   (32) aryl C₀₋₆ alkylcarbonylamino,    -   (33) C₁₋₆ alkylsulfonylamino,    -   (34) aryl C₀₋₆alkylsulfonylamino,    -   (35) C₁₋₆ alkoxycarbonylamino,    -   (36) aryl C₁₋₆ alkoxycarbonylamino,    -   (37) C₁₋₆alkylaminocarbonylamino,    -   (38) aryl C₀₋₆alkylaminocarbonylamino,    -   (39) (C₁₋₆alkyl)₂ aminocarbonylamino,    -   (40) (aryl C₀₋₆alkyl)₂ aminocarbonylamino,    -   (41) (C₁₋₆alkyl)₂ aminocarbonyloxy,    -   (42) C₀₋₆ alkyl carbonyl C₀₋₆ alkyl,    -   (43) aryl C₀₋₆ alkyl carbonyl C₀₋₆ alkyl, and    -   (44) (aryl C₀₋₆alkyl)₂ aminocarbonyloxy.

In a class of this embodiment of the present invention, R² is aryl,substituted with one to three substituents selected from:

-   -   (1) halogen,    -   (2) aryl,    -   (3) C₁₋₆ alkyl,    -   (4) C₃₋₈ cycloheteroalkyl,    -   (5) benzyl,    -   (6) amino,    -   (7) C₁₋₆ alkylamino,    -   (8) C₁₋₆ alkylthio,    -   (9) C₁₋₆ alkoxy,    -   (10) hydroxy,    -   (11) cyano,    -   (12) nitro,    -   (13) perfluoroC₁₋₄alkyl,    -   (14) trifluoromethoxy,    -   (15) oxo,    -   (16) methylcarbonyloxy,    -   (17) methylcarbonylamino,    -   (18) methylsulfonylamino,    -   (19) methoxycarbonylamino,    -   (20) methylaminocarbonylamino,    -   (21) dimethylaminocarbonylamino,    -   (22) dimethylaminocarbonyloxy. amd    -   (23) methylcarbonyl.

In a subclass of this embodiment of the present invention, R² is aryl,substituted by one or two substituents selected from:

-   -   (1) halogen,    -   (2) methyl,    -   (3) C₁₋₂ alkoxy,    -   (4) hydroxy,    -   (5) cyano,    -   (6) nitro,    -   (7) trifluoromethyl,    -   (8) trifluoromethoxy,    -   (9) methylcarbonyl,

In another subclass of this class of the present invention, R² is aryl,substituted by one substituents selected from:

-   -   (1) fluoro,    -   (2) chloro,    -   (3) bromo,    -   (4) methyl,    -   (5) methoxy,    -   (6) ethoxy,    -   (7) hydroxy,    -   (8) trifluoromethyl,    -   (9) trifluoromethoxy, and    -   (10) acetyl.

In one embodiment of the present invention, R² is selected from phenyl,naphthyl, pyridyl, pyrrolyl, pyrazolyl, pyrazinyl, pyrimidinyl,imidazolyl, benzimidazolyl, benzthiazolyl, benzoxazolyl, indolyl,thiophenyl, furanyl, dihydrobenzofuranyl, benzo(1,3)dioxolanyl,benzo(1,4)dioxanyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl,indanyl, isoquinolinyl, dihydroisoquinolinyl, tetrahydronaphthyridinyl,benzothienyl, imidazopyridinyl, tetrahydrobenzazepinyl, quinoxalinyl,imidazopyrimidinyl, cyclopentenopyridinyl, phthalazinyl,tetrahydroquinolinyl, oxindolyl, isoquinolinyl, imidazothiazolyl,dihydroimidazothiazolyl, tetrazolyl, triazolyl, pyridazinyl,piperidinyl, piperazinyl, oxadiazolyl, thiadiazolyl, triazinyl,indazolyl, indazolinone, dihydrobenzofuranyl, phthalide, phthalimide,coumarin, chromone, tetrahydroisoquindine, naphthyridinyl,tetrahydronaphthyridinyl, isoindolinyl, triazanaphthalinyl, pteridinyl,purinyl, and quinolinyl.

In one class of the present invention, R² is selected from: phenyl,naphthyl, quinolinyl, pyridyl, furanyl, thiophenyl, thiazolyl,pyrimidyl, oxazolyl, furanyl, and pyridazinyl, unsubstituted orsubstituted.

In a subclass of this class of the invention, R² is phenyl.

In another embodiment of the present invention, R² is C₁₋₈ alkyl,unsubstituted or substituted with one to three substituentsindependently selected from:

-   -   (1) halogen,    -   (2) C₁₋₈ alkyl,    -   (3) C₃₋₈ cycloalkyl,    -   (4) C₃₋₈ cycloheteroalkyl,    -   (5) amino,    -   (6) C₁₋₆ alkylamino,    -   (7) (C₁₋₆ alkyl)₂amino,    -   (8) aryl C₀₋₆ alkylamino,    -   (9) (aryl C₀₋₆ alkyl)₂amino,    -   (10) C₁₋₆ alkylthio,    -   (11) aryl C₀₋₆alkylthio,    -   (12) C₁₋₆ alkylsulfinyl,    -   (13) aryl C₀₋₆alkylsulfinyl,    -   (14) C₁₋₆ alkylsulfonyl,    -   (15) aryl C₀₋₆alkylsulfonyl,    -   (16) C₁₋₆ alkoxy,    -   (17) aryl C₀₋₆ alkoxy,    -   (18) hydroxycarbonyl,    -   (19) C₁₋₆ alkoxycarbonyl,    -   (20) aryl C₀₋₆ alkoxycarbonyl,    -   (21) hydroxycarbonyl C₁₋₆ alkyloxy,    -   (22) hydroxy,    -   (23) cyano,    -   (24) nitro,    -   (25) perfluoroC₁₋₄alkyl,    -   (26) perfluoroC₁₋₄alkoxy,    -   (27) oxo,    -   (28) C₁₋₆ alkylcarbonyloxy,    -   (29) aryl C₀₋₆alkylcarbonyloxy,    -   (30) alkyl C₁₋₆ carbonylamino,    -   (31) aryl C₀₋₆ alkylcarbonylamino,    -   (32) C₁₋₆ alkylsulfonylamino,    -   (33) aryl C₀₋₆alkylsulfonylamino,    -   (34) C₁₋₆ alkoxycarbonylamino,    -   (35) aryl C₀₋₆ alkoxycarbonylamino,    -   (36) C₁₋₆alkylaminocarbonylamino,    -   (37) aryl C₀₋₆alkylaminocarbonylamino,    -   (38) (C₁₋₆alkyl)₂ aminocarbonylamino,    -   (39) (aryl C₀₋₆alkyl)₂ aminocarbonylamino,    -   (40) (C₁₋₆alkyl)₂ aminocarbonyloxy,    -   (41) (aryl C₀₋₆alkyl)₂ aminocarbonyloxy, and    -   (42) spiro-C₃₋₈cycloalkyl.

In a class of this embodiment of the present invention, R² is C₁₋₆alkyl, unsubstituted or substituted with one to three substituentsindependently selected from:

-   -   (1) fluoro,    -   (2) chloro,    -   (3) C₃₋₆ cycloalkyl,    -   (4) C₃₋₆ cycloheteroalkyl,    -   (5) amino,    -   (6) C₁₋₆ alkylamino,    -   (7) (C₁₋₆ alkyl)₂amino,    -   (8) aryl C₀₋₆ alkylamino,    -   (9) (aryl C₀₋₆ alkyl)₂amino,    -   (10) C₁₋₆ alkylthio,    -   (11) aryl C₀₋₁alkylthio,    -   (12) C₁₋₆ alkylsulfinyl,    -   (13) aryl C₀₋₁alkylsulfinyl,    -   (14) C₁₋₆ alkylsulfonyl,    -   (15) aryl C₀₋₁alkylsulfonyl,    -   (16) C₁₋₆ alkoxy,    -   (17) aryl C₀₋₁ alkoxy,    -   (18) hydroxycarbonyl,    -   (19) C₁₋₆ alkoxycarbonyl,    -   (20) aryl C₀₋₁ alkoxycarbonyl,    -   (21) hydroxycarbonyl C₁₋₆ alkyloxy,    -   (22) hydroxy,    -   (23) cyano,    -   (24) nitro,    -   (25) perfluoroC₁₋₄alkyl,    -   (26) trifluoromethoxy,    -   (27) oxo,    -   (28) C₁₋₆ alkylcarbonyloxy,    -   (29) aryl C₀₋₁alkylcarbonyloxy,    -   (30) C₁₋₆ alkylcarbonylamino,    -   (31) aryl C₀₋₁ alkylcarbonylamino,    -   (32) C₁₋₆ alkylsulfonylamino,    -   (33) aryl C₀₋₁alkylsulfonylamino,    -   (34) C₁₋₆ alkoxycarbonylamino,    -   (35) aryl C₀₋₁ alkoxycarbonylamino,    -   (36) C₁₋₆alkylaminocarbonylamino,    -   (37) aryl C₀₋₁alkylaminocarbonylamino,    -   (38) (C₁₋₆alkyl)₂ aminocarbonylamino,    -   (39) (aryl C₀₋₁alkyl)₂ aminocarbonylamino,    -   (40) (C₁₋₆alkyl)₂ aminocarbonyloxy,    -   (41) (aryl C₀₋₁alkyl)₂ aminocarbonyloxy, and    -   (42) spiro-cyclopropyl.

In a subclass of this class of the present invention, R² is C₁₋₆ alkyl,unsubstituted or substituted with one or two substituents independentlyselected from:

-   -   (1) fluoro,    -   (2) chloro,    -   (3) cyano,    -   (4) methoxy,    -   (5) hydroxy, and    -   (6) trifluoromethyl.

In another subclass of this embodiment of the present invention, R² isselected from:

-   -   (1) methyl,    -   (2) ethyl,    -   (3) n-propyl,    -   (4) isopropyl,    -   (5) n-butyl,    -   (6) sec-butyl,    -   (7) t-butyl, and    -   (8) n-hexyl,        unsubstituted or substituted with one or two substituents        independently selected from:    -   (a) fluoro,    -   (b) chloro,    -   (c) cyano,    -   (d) methoxy,    -   (e) hydroxy, and    -   (f) trifluoromethyl.

In another embodiment of the present invention, R² is perfluoroC₁₋₈alkyl. In one class of this embodiment of the present invention R² isperfluoroC₁₋₃ alkyl. In a subclass of this embodiment of the presentinvention, R² is trifluoromethyl.

In yet another embodiment of the present invention, R² is aryl-C₁₋₆alkyl-, wherein aryl is unsubstituted or substituted with 1 to 3substituents independently selected from:

-   -   (1) halogen,    -   (2) C₁₋₈ alkyl,    -   (3) C₃₋₈ cycloalkyl,    -   (4) aryl,    -   (5) aryl C₁₋₃ alkyl-,    -   (6) amino,    -   (7) amino C₁₋₆ alkyl-,    -   (8) C₁₋₃ acylamino,    -   (9) C₁₋₃ acylamino C₁₋₆ alkyl,    -   (10) C₁₋₆ alkylamino,    -   (11) C₁₋₆ alkylamino C₁₋₆ alkyl,    -   (12) di(C₁₋₆) alkylamino,    -   (13) di(C₁₋₆) alkylamino-C₁₋₆ alkyl,    -   (14) C₁₋₄ alkoxy,    -   (15) C₁₋₄ alkylthio,    -   (16) C₁₋₄ alkylsulfinyl,    -   (17) C₁₋₄ alkylsulfonyl,    -   (18) C₁₋₄ alkoxy C₁₋₆ alkyl,    -   (19) hydroxycarbonyl,    -   (20) hydroxycarbonyl C₁₋₆ alkyl,    -   (21) C₁₋₅ alkoxycarbonyl,    -   (22) C₁₋₃ alkoxycarbonyl C₁₋₆ alkyl,    -   (23) hydroxycarbonyl C₁₋₆ alkyloxy,    -   (24) hydroxy,    -   (25) hydroxy C₁₋₆ alkyl,    -   (26) cyano,    -   (27) nitro,    -   (28) trifluoromethyl,    -   (29) trifluoromethoxy,    -   (30) C₁₋₅ alkylcarbonyloxy;        and wherein alkyl is substituted with one to three substituents        selected from:    -   (1) halogen,    -   (2) C₃₋₈ cycloalkyl,    -   (3) C₃₋₈ cycloheteroalkyl,    -   (4) amino,    -   (5) C₁₋₆ alkylamino,    -   (6) (C₁₋₆ alkyl)₂amino,    -   (7) aryl C₀₋₆ alkylamino,    -   (8) (aryl C₀₋₆ alkyl)₂amino,    -   (9) C₁₋₆ alkylthio,    -   (10) aryl C₀₋₆ alkylthio,    -   (11) C₁₋₆ alkylsulfinyl,    -   (12) aryl C₀₋₆alkylsulfinyl,    -   (13) C₁₋₆ alkylsulfonyl,    -   (14) aryl C₀₋₆ alkylsulfonyl,    -   (15) C₁₋₆ alkoxy,    -   (16) aryl C₀₋₆ alkoxy,    -   (17) hydroxycarbonyl,    -   (18) C₁₋₆ alkoxycarbonyl,    -   (19) aryl C₀₋₆ alkoxycarbonyl,    -   (20) hydroxycarbonyl C₁₋₆ alkyloxy,    -   (21) hydroxy,    -   (22) cyano,    -   (23) nitro,    -   (24) trifluoroalkyl,    -   (25) trifluoroalkoxy,    -   (26) oxo,    -   (27) C₁₋₆ alkylcarbonyloxy,    -   (28) aryl C₀₋₆ alkylcarbonyloxy,    -   (29) C₁₋₆ alkylcarbonylamino,    -   (30) aryl C₀₋₆ alkylcarbonylamino,    -   (31) C₁₋₆ alkylsulfonylamino,    -   (32) aryl C₀₋₆ alkylsulfonylamino,    -   (33) C₁₋₆ alkoxycarbonylamino,    -   (34) aryl C₀₋₆ alkoxycarbonylamino,    -   (35) C₁₋₆ alkylaminocarbonylamino,    -   (36) aryl C₀₋₆ alkylaminocarbonylamino,    -   (37) (C₁₋₆ alkyl)₂ aminocarbonylamino,    -   (38) (aryl C₀₋₆ alkyl)₂ aminocarbonylamino,    -   (39) (C₁₋₆ alkyl)₂ aminocarbonyloxy,    -   (40) (aryl C₀₋₆ alkyl)₂ aminocarbonyloxy, and    -   (41) spiro-C₃₋₈ cycloalkyl.

In one class of this embodiment, R² is phenyl-C₁₋₆ alkyl-, whereinphenyl is unsubstituted or substituted with one or two substituentsindependently selected from:

-   -   (1) halogen,    -   (2) C₁₋₃ alkyl,    -   (3) C₃₋₆ cycloalkyl,    -   (4) phenyl,    -   (5) phenyl C₁₋₃ alkyl-,    -   (6) amino,    -   (7) amino C₁₋₆ alkyl-,    -   (8) C₁₋₃ acylamino,    -   (9) C₁₋₃ acylamino C₁₋₆ alkyl,    -   (10) C₁₋₆ alkylamino,    -   (11) C₁₋₆ alkylamino C₁₋₆ alkyl,    -   (12) di(C₁₋₆) alkylamino,    -   (13) di(C₁₋₆) alkylamino-C₁₋₆ alkyl,    -   (14) C₁₋₂ alkoxy,    -   (15) C₁₋₂ alkylthio,    -   (16) C₁₋₂ alkylsulfinyl,    -   (17) C₁₋₂ alkylsulfonyl,    -   (18) C₁₋₂ alkoxy C₁₋₆ alkyl,    -   (19) hydroxycarbonyl,    -   (20) hydroxycarbonyl C₁₋₆ alkyl,    -   (21) C₁₋₅ alkoxycarbonyl,    -   (22) C₁₋₃ alkoxycarbonyl C₁₋₆ alkyl,    -   (23) hydroxycarbonyl C₁₋₆ alkyloxy,    -   (24) hydroxy,    -   (25) hydroxy C₁₋₆ alkyl,    -   (26) cyano,    -   (27) nitro,    -   (28) trifluoromethyl,    -   (29) trifluoromethoxy, and    -   (30) C₁₋₅ alkylcarbonyloxy;        and wherein alkyl is substituted with one to three substituents        selected from:    -   (1) halogen,    -   (2) C₃₋₈ cycloalkyl,    -   (3) C₃₋₈ cycloheteroalkyl,    -   (4) amino,    -   (5) methylalkylamino,    -   (6) dimethylamino,    -   (7) phenylamino,    -   (8) (phenyl)₂amino,    -   (9) methylthio,    -   (10) phenylthio,    -   (11) methylsulfinyl,    -   (12) phenylsulfinyl,    -   (13) methylsulfonyl,    -   (14) phenylsulfonyl,    -   (15) C₁₋₃ alkoxy,    -   (16) benzyloxy,    -   (17) hydroxycarbonyl,    -   (18) methyloxycarbonyl,    -   (19) phenyloxycarbonyl,    -   (20) hydroxycarbonyl C₁₋₆ alkyloxy,    -   (21) hydroxy,    -   (22) cyano,    -   (23) nitro,    -   (24) trifluoroalkyl,    -   (25) trifluoroalkoxy,    -   (26) oxo,    -   (27) methylcarbonyloxy,    -   (28) phenylcarbonyloxy,    -   (29) methylcarbonylamino,    -   (30) phenylcarbonylamino,    -   (31) methylsulfonylamino,    -   (32) phenylsulfonylamino,    -   (33) methoxycarbonylamino,    -   (34) phenyloxycarbonylamino,    -   (35) dimethylaminocarbonylamino,    -   (36) phenylaminocarbonylamino,    -   (37) dimethyl aminocarbonylamino,    -   (38) diphenyl aminocarbonylamino,    -   (39) dimethyl aminocarbonyloxy,    -   (40) diphenyl aminocarbonyloxy, and    -   (41) spiro-C₃₋₈ cycloalkyl.

In one class of this embodiment, R² is phenyl-C₁₋₆ alkyl-, whereinphenyl is unsubstituted or substituted with one or two substituentsindependently selected from:

-   -   (1) halogen,    -   (2) methyl,    -   (3) C₁₋₂ alkoxy,    -   (4) hydroxy,    -   (5) nitro,    -   (6) trifluoromethyl, and    -   (7) trifluoromethoxy.

In still another embodiment of the present invention, R² is C₂₋₈alkenyl, unsubstituted or substituted with one to three substituentsindependently selected from:

-   -   (a) halogen,    -   (b) C₁₋₈ alkyl,    -   (c) C₃₋₈ cycloalkyl,    -   (d) C₃₋₈ cycloheteroalkyl,    -   (e) amino,    -   (f) C₁₋₆ alkylamino,    -   (g) (C₁₋₆ alkyl)₂amino,    -   (h) aryl C₀₋₆ alkylamino,    -   (i) (aryl C₀₋₆ alkyl)₂amino,    -   (j) C₁₋₆ alkylthio,    -   (k) aryl C₀₋₆alkylthio,    -   (l) C₁₋₆ alkylsulfinyl,    -   (m) aryl C₀₋₆alkylsulfinyl,    -   (n) C₁₋₆ alkylsulfonyl,    -   (o) aryl C₀₋₆alkylsulfonyl,    -   (p) C₁₋₆ alkoxy,    -   (q) aryl C₀₋₆ alkoxy,    -   (r) hydroxycarbonyl,    -   (s) C₁₋₆ alkoxycarbonyl,    -   (t) aryl C₀₋₆ alkoxycarbonyl,    -   (u) hydroxycarbonyl C₁₋₆ alkyloxy,    -   (v) hydroxy,    -   (w) cyano,    -   (x) nitro,    -   (y) perfluoroC₁₋₄alkyl,    -   (z) perfluoroC₁₋₄alkoxy,    -   (aa) oxo,    -   (bb) C₁₋₆ alkylcarbonyloxy,    -   (cc) aryl C₀₋₆alkylcarbonyloxy,    -   (dd) C₁₋₆ alkylcarbonylamino,    -   (ee) aryl C₀₋₆ alkylcarbonylamino,    -   (ff) C₁₋₆ alkylsulfonylamino,    -   (gg) aryl C₀₋₆alkylsulfonylamino,    -   (hh) C₁₋₆ alkoxycarbonylamino,    -   (ii) aryl C₀₋₆ alkoxycarbonylamino,    -   (jj) C₁₋₆alkylaminocarbonylamino,    -   (kk) aryl C₀₋₆alkylaminocarbonylamino,    -   (ll) (C₁₋₆alkyl)₂ aminocarbonylamino,    -   (mm) (aryl C₀₋₆alkyl)₂ aminocarbonylamino,    -   (nn) (C₁₋₆alkyl)₂ aminocarbonyloxy,    -   (oo) (aryl C₀₋₆alkyl)₂ aminocarbonyloxy, and    -   (pp) spiro-C₃₋₈cycloalkyl.

In one class of this embodiment of the present invention, R² is C₂₋₃alkenyl, unsubstituted or substituted with one to two substituentsindependently selected from:

-   -   (a) fluoro,    -   (b) chloro,    -   (c) methyloxy,    -   (d) hydroxy,    -   (e) cyano,    -   (f) nitro,    -   (g) trifluoromethyl,    -   (h) trifluoromethoxy, and    -   (i) oxo.

In one subclass of this class of this embodiment of the presentinvention, R² is C₂₋₃ alkenyl.

In still another embodiment of the present invention, R² is aryl C₂₋₈alkenyl, wherein aryl is unsubstituted or substituted with one to threesubstituents independently selected from:

-   -   (1) halogen,    -   (2) C₁₋₈ alkyl,    -   (3) C₃₋₈ cycloalkyl,    -   (4) aryl,    -   (5) aryl C₁₋₃ alkyl-,    -   (6) amino,    -   (7) amino C₁₋₆ alkyl-,    -   (8) C₁₋₃ acylamino,    -   (9) C₁₋₃ acylamino C₁₋₆ alkyl,    -   (10) C₁₋₆ alkylamino,    -   (11) C₁₋₆ alkylamino C₁₋₆ alkyl,    -   (12) di(C₁₋₆) alkylamino,    -   (13) di(C₁₋₆) alkylamino-C₁₋₆ alkyl,    -   (14) C₁₋₄ alkoxy,    -   (15) C₁₋₄ alkylthio,    -   (16) C₁₋₄ alkylsulfinyl,    -   (17) C₁₋₄ alkylsulfonyl,    -   (18) C₁₋₄ alkoxy C₁₋₆ alkyl,    -   (19) hydroxycarbonyl,    -   (20) hydroxycarbonyl C₁₋₆ alkyl,    -   (21) C₁₋₅ alkoxycarbonyl,    -   (22) C₁₋₃ alkoxycarbonyl C₁₋₆ alkyl,    -   (23) hydroxycarbonyl C₁₋₆ alkyloxy,    -   (24) hydroxy,    -   (25) hydroxy C₁₋₆ alkyl,    -   (26) cyano,    -   (27) nitro,    -   (28) trifluoromethyl,    -   (29) trifluoromethoxy, and    -   (30) C₁₋₅ alkylcarbonyloxy.

In a class of this embodiment, R² is phenyl C₂₋₈ alkenyl, wherein phenylis unsubstituted or substituted with one to three substituentsindependently selected from:

-   -   (1) halogen,    -   (2) C₁₋₃ alkyl,    -   (3) C₃₋₆ cycloalkyl,    -   (4) phenyl,    -   (5) phenyl C₁₋₃ alkyl-,    -   (6) amino,    -   (7) amino C₁₋₆ alkyl-,    -   (8) C₁₋₃ acylamino,    -   (9) C₁₋₃ acylamino C₁₋₆ alkyl,    -   (10) C₁₋₆ alkylamino,    -   (11) C₁₋₆ alkylamino C₁₋₆ alkyl,    -   (12) di(C₁₋₆) alkylamino,    -   (13) di(C₁₋₆) alkylamino-C₁₋₆ alkyl,    -   (14) C₁₋₂ alkoxy,    -   (15) C₁₋₂ alkylthio,    -   (16) C₁₋₂ alkylsulfinyl,    -   (17) C₁₋₂ alkylsulfonyl,    -   (18) C₁₋₂ alkoxy C₁₋₆ alkyl,    -   (19) hydroxycarbonyl,    -   (20) hydroxycarbonyl C₁₋₆ alkyl,    -   (21) C₁₋₅ alkoxycarbonyl,    -   (22) C₁₋₃ alkoxycarbonyl C₁₋₆ alkyl,    -   (23) hydroxycarbonyl C₁₋₆ alkyloxy,    -   (24) hydroxy,    -   (25) hydroxy C₁₋₆ alkyl,    -   (26) cyano,    -   (27) nitro,    -   (28) trifluoromethyl,    -   (29) trifluoromethoxy, and    -   (30) C₁₋₅ alkylcarbonyloxy;

In a subclass of this class, R² is phenyl C₂₋₃ alkenyl, wherein phenylis unsubstituted or substituted with one to two substituentsindependently selected from:

-   -   (1) halogen,    -   (2) methyl,    -   (3) C₁₋₂ alkoxy,    -   (4) hydroxy,    -   (5) nitro,    -   (6) trifluoromethyl, and    -   (7) trifluoromethoxy.

In another subclass of this class, R² is phenyl ethenyl, wherein phenylis unsubstituted or substituted with a substituent selected from:

-   -   (1) halogen,    -   (2) methyl, and    -   (3) trifluoromethyl.

In yet still another embodiment of the present invention, R² is C₃₋₈cycloalkyl, either unsubstituted or substituted with one to threesubstituents selected from:

-   -   (1) halogen,    -   (2) aryl,    -   (3) C₁₋₈ alkyl,    -   (4) C₃₋₈ cycloalkyl,    -   (5) C₃₋₈ cycloheteroalkyl,    -   (6) aryl C₁₋₆alkyl,    -   (7) amino C₀₋₆alkyl,    -   (8) C₁₋₆ alkylamino C₀₋₆alkyl,    -   (9) (C₁₋₆ alkyl)₂amino C₀₋₆alkyl,    -   (10) aryl C₀₋₆ alkylamino C₀₋₆alkyl,    -   (11) (aryl C₀₋₆ alkyl)₂amino C₀₋₆alkyl,    -   (12) C₁₋₆ alkylthio,    -   (13) aryl C₀₋₆alkylthio,    -   (14) C₁₋₆ alkylsulfinyl,    -   (15) aryl C₀₋₆alkylsulfinyl,    -   (16) C₁₋₆ alkylsulfonyl,    -   (17) aryl C₀₋₆alkylsulfonyl,    -   (18) C₁₋₆ alkoxy C₀₋₆alkyl,    -   (19) aryl C₀₋₆ alkoxy C₀₋₆alkyl,    -   (20) hydroxycarbonyl C₀₋₆alkyl,    -   (21) C₁₋₆ alkoxycarbonyl C₀₋₆alkyl,    -   (22) aryl C₀₋₆ alkoxycarbonyl C₀₋₆alkyl,    -   (23) hydroxycarbonyl C₁₋₆ alkyloxy,    -   (24) hydroxy C₀₋₆alkyl,    -   (25) cyano,    -   (26) nitro,    -   (27) perfluoroC₁₋₄alkyl,    -   (28) perfluoroC₁₋₄alkoxy,    -   (29) oxo,    -   (30) C₁₋₆ alkylcarbonyloxy,    -   (31) aryl C₀₋₆alkylcarbonyloxy,    -   (32) alkyl C₁₋₆ carbonylamino,    -   (33) aryl C₀₋₆ alkylcarbonylamino,    -   (34) C₁₋₆ alkylsulfonylamino,    -   (35) aryl C₀₋₆alkylsulfonylamino,    -   (36) C₁₋₆ alkoxycarbonylamino,    -   (37) aryl C₀₋₆ alkoxycarbonylamino,    -   (38) C₁₋₆alkylaminocarbonylamino,    -   (39) aryl C₀₋₆alkylaminocarbonylamino,    -   (40) (C₁₋₆alkyl)₂ aminocarbonylamino,    -   (41) (aryl C₀₋₆alkyl)₂ aminocarbonylamino,    -   (42) (C₁₋₆alkyl)₂ aminocarbonyloxy,    -   (43) (aryl C₀₋₆alkyl)₂ aminocarbonyloxy,    -   (44) C₀₋₆ alkylcarbonyl C₀₋₆ alky, and    -   (45) spiro-C₃₋₈cycloalkyl.

In a class of this embodiment, R² is C₃₋₈ cycloalkyl, eitherunsubstituted or substituted with one to three substituents selectedfrom:

-   -   (1) halogen,    -   (2) phenyl,    -   (3) C₁₋₄₆ alkyl,    -   (4) C₃₋₈ cycloheteroalkyl,    -   (5) benzyl,    -   (6) amino,    -   (7) C₁₋₄ alkylamino,    -   (8) C₁₋₄ alkylthio,    -   (9) C₁₋₄ alkoxy,    -   (10) hydroxy,    -   (11) cyano,    -   (12) nitro,    -   (13) perfluoroC₁₋₄alkyl,    -   (14) trifluoromethoxy,    -   (15) oxo,    -   (16) methylcarbonyloxy,    -   (17) methylcarbonylamino,    -   (18) methylsulfonylamino,    -   (19) methoxycarbonylamino,    -   (20) methylaminocarbonylamino,    -   (21) dimethylaminocarbonylamino,    -   (22) dimethylaminocarbonyloxy, and    -   (23) spiro C₃₋₈ cycloalkyl.

In a subclass of this class of the present invention, R² is selectedfrom cyclopropyl and cyclohexyl, either unsubstituted or substitutedwith one to three substituents selected from:

-   -   (1) fluoro,    -   (2) phenyl,    -   (3) methyl,    -   (4) trifluoromethyl,    -   (5) methoxy,    -   (6) hydroxy,    -   (7) oxo, and    -   (8) spiro C₃₋₈ cycloalkyl.

In another subclass of this class of the present invention, R² isselected from cyclopropyl and cyclohexyl, either unsubstituted orsubstituted with one to two substituents selected from:

-   -   (a) fluoro,    -   (b) chloro,    -   (c) phenyl,    -   (d) methyl,    -   (e) C₁₋₃ alkylamino,    -   (f) C₁₋₃ alkoxy,    -   (g) hydroxy,    -   (h) trifluoromethyl,    -   (i) trifluoromethoxy, and    -   (j) oxo.

In another embodiment of the present invention, R² is cycloheteroalkyl,unsubstituted or substituted with one to three substituents selectedfrom:

-   -   (a) halogen,    -   (b) aryl,    -   (c) C₁₋₈ alkyl,    -   (d) C₃₋₈ cycloalkyl,    -   (e) C₃₋₈ cycloheteroalkyl,    -   (f) aryl C₁₋₆alkyl,    -   (g) amino C₀₋₆alkyl,    -   (h) C₁₋₆ alkylamino C₀₋₆alkyl,    -   (i) (C₁₋₆ alkyl)₂amino C₀₋₆alkyl,    -   (j) aryl C₀₋₆ alkylamino C₀₋₆alkyl,    -   (k) (aryl C₀₋₆ alkyl)₂amino C₀₋₆alkyl,    -   (l) C₁₋₆ alkylthio,    -   (m) aryl C₀₋₆alkylthio,    -   (n) C₁₋₆ alkylsulfinyl,    -   (o) aryl C₀₋₆alkylsulfinyl,    -   (p) C₁₋₆ alkylsulfonyl,    -   (q) aryl C₀₋₆alkylsulfonyl,    -   (r) C₁₋₆ alkoxy C₀₋₆alkyl,    -   (s) aryl C₀₋₆ alkoxy C₀₋₆alkyl,    -   (t) hydroxycarbonyl C₀₋₆alkyl,    -   (u) C₁₋₆ alkoxycarbonyl C₀₋₆alkyl,    -   (v) aryl C₀₋₆ alkoxycarbonyl C₀₋₆alkyl,    -   (w) hydroxycarbonyl C₁₋₆ alkyloxy,    -   (x) hydroxy C₀₋₆alkyl,    -   (y) cyano,    -   (z) nitro,    -   (aa) perfluoroC₁₋₄alkyl,    -   (bb) perfluoroC₁₋₄alkoxy,    -   (cc) oxo,    -   (dd) C₁₋₆ alkylcarbonyloxy,    -   (ee) aryl C₀₋₆alkylcarbonyloxy,    -   (ff) C₁₋₆ alkylcarbonylamino,    -   (gg) aryl C₀₋₆ alkylcarbonylamino,    -   (hh) C₁₋₆ alkylsulfonylamino,    -   (ii) aryl C₀₋₆alkylsulfonylamino,    -   (jj) C₁₋₆ alkoxycarbonylamino,    -   (kk) aryl C₀₋₆ alkoxycarbonylamino,    -   (ll) C₁₋₆alkylaminocarbonylamino,    -   (mm) aryl C₀₋₆alkylaminocarbonylamino,    -   (nn) (C₁₋₆alkyl)₂ aminocarbonylamino,    -   (oo) (aryl C₀₋₆alkyl)₂ aminocarbonylamino,    -   (pp) (C₁₋₆alkyl)₂ aminocarbonyloxy,    -   (qq) (aryl C₀₋₆alkyl)₂ aminocarbonyloxy,    -   (rr) C₀₋₆ alkylcarbonylC₀₋₆ alkyl, and    -   (ss) spiro-C₃₋₈cycloalkyl;        provided that any heteroatom substituent is bonded to a carbon        atom in the cycloheteroalkyl ring.

In one class of this embodiment of the present invention, R² iscycloheteroalkyl, unsubstituted or substituted with one to twosubstituents selected from:

-   -   (a) fluoro,    -   (b) chloro,    -   (c) phenyl,    -   (d) C₁₋₄ alkyl,    -   (e) benzyl,    -   (f) amino,    -   (g) C₁₋₆ alkylamino,    -   (h) C₁₋₆ alkylthio,    -   (i) C₁₋₆ alkoxy,    -   (j) hydroxy,    -   (k) cyano,    -   (l) nitro,    -   (m) perfluoroC₁₋₄alkyl,    -   (n) trifluoromethoxy,    -   (o) oxo,    -   (p) methylcarbonyloxy,    -   (q) methylcarbonylamino,    -   (r) methylsulfonylamino,    -   (s) methoxycarbonylamino,    -   (t) methylaminocarbonylamino,    -   (u) dimethylaminocarbonylamino,    -   (v) dimethylaminocarbonyloxy, and    -   (w) spiro C₃₋₈ cycloalkyl,        provided that any heteroatom substituent is bonded to a carbon        atom in the cycloheteroalkyl ring.

In a subclass of this class of the present invention, R² iscycloheteroalkyl, either unsubstituted or substituted with one or twosubstituents selected from:

-   -   (a) fluoro,    -   (b) phenyl,    -   (c) C₁₋₄ alkyl,    -   (d) C₁₋₃ alkoxy,    -   (e) hydroxy,    -   (f) trifluoromethyl,    -   (g) oxo, and    -   (h) spiro C₃₋₈ cycloalkyl;        provided that any heteroatom substituent is bonded to a carbon        atom in the cycloheteroalkyl ring.

In another subclass of this class of the present invention, R² iscycloheteroalkyl, either unsubstituted or substituted with one to twosubstituents selected from:

-   -   (a) fluoro,    -   (b) chloro,    -   (c) phenyl,    -   (d) C₁₋₄ alkyl,    -   (e) C₁₋₃ alkoxy,    -   (f) hydroxy,    -   (g) trifluoromethyl,    -   (h) trifluoromethoxy, and    -   (i) oxo.        provided that any heteroatom substituent is bonded to a carbon        atom in the cycloheteroalkyl ring.

In one subclass, R² is selected from piperidinyl, pyrrolidinyl,azetidinyl, morpholinyl, piperazinyl, tetrahydrofuranyl, andoctahydroquinolizinyl, either unsubstituted or substituted. In anothersubclass, R² is selected from: tetrahydrofuranyl, piperidinyl,pyrrolidinyl, morpholinyl, and octahydro-2H-quinolizinyl, eitherunsubstituted or substituted. In still another subclass of the presentinvention, R² is tetrahydrofuranyl.

R³ is selected from H, perfluoro C₁₋₈ alkyl, and C₁₋₈ alkyl,unsubstituted or substituted with one to three halogen atoms, or R² andR³, together with the nitrogen atom and “X” moiety to which they areattached, form a 5- to 7-membered heterocyclic ring, optionallycontaining one or two additional heteroatoms selected from N, S, and O,optionally having one or more degrees of unsaturation, optionally fusedto a 6-membered heteroaromatic or aromatic ring, either unsubstituted orsubstituted with one to three substituents selected from:

-   -   (1) halogen,    -   (2) aryl,    -   (3) C₁₋₈alkyl,    -   (4) C₃₋₈ cycloalkyl,    -   (5) C₃₋₈ cycloheteroalkyl,    -   (6) aryl C₁₋₆alkyl,    -   (7) amino C₀₋₆alkyl,    -   (8) C₁₋₆ alkylamino C₀₋₆alkyl,    -   (9) (C₁₋₆ alkyl)₂amino C₀₋₆alkyl,    -   (10) aryl C₀₋₆ alkylamino C₀₋₆alkyl,    -   (11) (aryl C₀₋₆ alkyl)₂amino C₀₋₆alkyl,    -   (12) C₁₋₆ alkylthio,    -   (13) aryl C₀₋₆alkylthio,    -   (14) C₁₋₆ alkylsulfinyl,    -   (15) aryl C₀₋₆alkylsulfinyl,    -   (16) C₁₋₆ alkylsulfonyl,    -   (17) aryl C₀₋₆alkylsulfonyl,    -   (18) C₁₋₆ alkoxy C₀₋₆alkyl,    -   (19) aryl C₀₋₆ alkoxy C₀₋₆alkyl,    -   (20) hydroxycarbonyl C₀₋₆alkyl,    -   (21) C₁₋₆ alkoxycarbonyl C₀₋₆alkyl,    -   (22) aryl C₀₋₆ alkoxycarbonyl C₀₋₆alkyl,    -   (23) hydroxycarbonyl C₁₋₆ alkyloxy,    -   (24) hydroxy C₀₋₆alkyl,    -   (25) cyano,    -   (26) nitro,    -   (27) perfluoroC₁₋₄alkyl,    -   (28) perfluoroC₁₋₄alkoxy,    -   (29) oxo,    -   (30) C₁₋₆ alkylcarbonyloxy,    -   (31) aryl C₁₋₆alkylcarbonyloxy,    -   (32) C₁₋₆ alkylcarbonylamino,    -   (33) aryl C₀₋₆ alkylcarbonylamino,    -   (34) C₁₋₆ alkylsulfonylamino,    -   (35) aryl C₀₋₆alkylsulfonylamino,    -   (36) C₁₋₆ alkoxycarbonylamino,    -   (37) aryl C₀₋₆ alkoxycarbonylamino,    -   (38) C₁₋₆alkylaminocarbonylamino,    -   (39) aryl C₀₋₆alkylaminocarbonylamino,    -   (40) (C₁₋₆alkyl)₂ aminocarbonylamino,    -   (41) (aryl C₀₋₆alkyl)₂ aminocarbonylamino,    -   (42) (C₁₋₆alkyl)₂ aminocarbonyloxy,    -   (43) (aryl C₀₋₆alkyl)₂ aminocarbonyloxy, and    -   (44) spiro-C₃₋₈cycloalkyl        provided that any heteroatom substituent is bonded to a carbon        atom in the heterocyclic ring;

In embodiment of the present invention, R³ is selected from H, perfluoroC₁₋₈ alkyl, and C₁₋₈ alkyl, unsubstituted or substituted with one tothree halogen atoms.

In class of this embodiment, R³ is selected from H, perfluoro C₁₋₃alkyl, and C₁₋₃ alkyl. In a subclass of this class, R³ is selected fromH, trifluoromethyl, and methyl. In a further subclass of the presentinvention, R³ is hydrogen.

In another embodiment of the present invention, R² and R³, together withthe nitrogen atom to which they are attached, form a 5- to 7-memberedheterocyclic ring, optionally containing one additional heteroatomselected from N, S, and O, optionally fused to a phenyl ring, optionallyhaving one or more degrees of unsaturation, either unsubstituted orsubstituted with one to two substituents selected from:

(1) halogen,

-   -   (2) phenyl,    -   (3) C₁₋₃ alkyl,    -   (4) methoxy,    -   (5) hydroxy,    -   (6) cyano,    -   (7) nitro,    -   (8) trifluoromethyl,    -   (9) trifluoromethoxy, and    -   (10) oxo,        provided that any heteroatom substituent is bonded to a carbon        atom in the heterocyclic ring.

In one class of this embodiment of the present invention, R² and R³,together with the nitrogen atom to which they are attached, form a C₅₋₇heterocyclic ring, optionally fused to a phenyl ring, unsubstituted, orsubstituted with one to three substituents selected from:

-   -   (1) fluoro,    -   (2) chloro,    -   (3) phenyl,    -   (4) methyl,    -   (5) methoxy,    -   (6) hydroxy,    -   (7) cyano,    -   (8) nitro,    -   (9) trifluoromethyl,    -   (10) trifluoromethoxy,    -   (11) oxo,        provided that any heteroatom substituent is bonded to a carbon        atom in the heterocyclic ring.

In one subclass of this embodiment, R² and R³ together form a groupselected from: indolinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl,piperidinyl, and pyrrolidinyl, unsubstituted or substituted with one tothree substituents selected from:

-   -   (1) fluoro,    -   (2) chloro,    -   (3) phenyl,    -   (4) methyl,    -   (5) methoxy,    -   (6) hydroxy,    -   (7) cyano,    -   (8) nitro,    -   (9) trifluoromethyl,    -   (10) trifluoromethoxy, and    -   (11) oxo,        provided that any heteroatom substituent is bonded to a carbon        atom in the heterocyclic ring.

In one embodiment of the present invention, R⁴ and R⁵ are eachindependently selected from

-   -   (1) hydrogen,    -   (2) halogen,    -   (3) phenyl,    -   (4) C₁₋₆ alkyl,    -   (5) cyclopropyl    -   (6) cyclohexyl,    -   (7) C₅₋₇ cycloheteroalkyl,    -   (8) benzyl,    -   (9) amino,    -   (10) C₁₋₆ alkylamino,    -   (11) (C₁₋₆ alkyl)₂amino,    -   (12) aryl amino,    -   (13) (aryl)₂amino,    -   (14) C₁₋₆ alkylthio,    -   (15) arylthio,    -   (16) C₁₋₆ alkoxy,    -   (17) aryl oxy,    -   (18) hydroxycarbonyl,    -   (19) C₁₋₆ alkoxycarbonyl,    -   (20) aryl C₀₋₆ alkoxycarbonyl,    -   (21) hydroxycarbonyl C₁₋₆ alkyloxy,    -   (22) hydroxy,    -   (23) cyano,    -   (24) nitro,    -   (25) trifluoromethoxy,    -   (26) trifluoromethyl,    -   (27) C₁₋₆ alkylcarbonyloxy,    -   (28) aryl C₀₋₆alkylcarbonyloxy,    -   (29) alkyl C₁₋₆ carbonylamino,    -   (30) aryl C₀₋₆ alkylcarbonylamino,    -   (31) C₁₋₆ alkoxycarbonylamino,    -   (32) aryl C₀₋₆ alkoxycarbonylamino,    -   (33) C₁₋₆alkylaminocarbonylamino,    -   (34) aryl C₀₋₆alkylaminocarbonylamino,    -   (35) (C₁₋₆alkyl)₂ aminocarbonylamino,    -   (36) (aryl C₀₋₆alkyl)₂ aminocarbonylamino,    -   (37) (C₁₋₆alkyl)₂ aminocarbonyloxy,    -   (38) C₀₋₆alkylcarbonyl C₀₋₆alkyl, and    -   (39) (aryl C₀₋₆alkyl)₂ aminocarbonyloxy,    -   or, R⁴ and R⁵ together form an oxo group or ═CH—R⁶ or a spiro        C₃₋₇ cycloalkyl ring substituted with R⁶.

In another embodiment of the present invention, R⁴ and R⁵ are eachindependently selected from:

-   -   (1) hydrogen,    -   (2) fluoro,    -   (3) chloro,    -   (4) phenyl,    -   (5) C₁₋₃ alkyl,    -   (6) cyclopropyl    -   (7) benzyl,    -   (8) amino,    -   (9) C₁₋₃ alkoxy,    -   (10) phenyloxy,    -   (11) hydroxycarbonyl,    -   (12) hydroxy,    -   (13) cyano,    -   (14) nitro,    -   (15) trifluoromethoxy, and    -   (16) trifluoromethyl,        or, R⁴ and R⁵ together form an oxo group or ═CH—R⁶ or a spiro        C₃₋₇ cycloalkyl ring substituted with R⁶.        In a class of this embodiment of the present invention, R⁴ and        R⁵ are each independently selected from    -   (1) hydrogen,    -   (2) fluoro,    -   (3) chloro,    -   (4) methyl,    -   (5) ethyl,    -   (6) methoxy,    -   (7) hydroxy,    -   (8) trifluoromethoxy, and    -   (9) trifluoromethyl,    -   or R⁴ and R⁵ together form an oxo group.

In a subclass of this class, R⁴ and R⁵ are each hydrogen.

In one embodiment of the present invention R⁶ is selected from hydrogenand methyl. In one class of this subclass, R⁶ is hydrogen.

In embodiment of the present invention, R⁷ is selected from hydrogen,perfluoro C₁₋₈ alkyl, and C₁₋₈ alkyl, unsubstituted or substituted withone to three fluoro or chloro substituents.

In class of this embodiment, R⁷ is selected from hydrogen, perfluoroC₁₋₃ alkyl, and C₁₋₃ alkyl. In a subclass of this class, R⁷ is selectedfrom hydrogen, trifluoromethyl, and methyl. In a further subclass of thepresent invention, R⁷ is hydrogen.

In one embodiment of the present invention, n is 2. In anotherembodiment of the present invention, n is 0. In yet another embodimentof the present invention, n is 1.

Particular compounds of structural formula (I) include:

-   (1)    4-methyl-17β-(2-trifluoromethylbenzamido)-4-aza-5α-androst-1-ene-3-one;-   (2)    4-methyl-17β-(3-trifluoromethylbenzamido)-4-aza-5α-androst-1-ene-3-one;-   (3) 4-methyl-17β-(2-methoxybenzamido)-4-aza-5α-androst-1-ene-3-one;-   (4) 4-methyl-17β-(3-methoxybenzamido)-4-aza-5α-androst-1-ene-3-one;-   (5) 4-methyl-17β-(4-methoxybenzamido)-4-aza-5α-androst-1-ene-3-one;-   (6) 4-methyl-17β-(4-cyanobenzamido)-4-aza-5α-androst-1-ene-3-one;-   (7)    4-methyl-17β-(2-chloro-pyrid-3-yl-amido)-4-aza-5α-androst-1-ene-3-one;-   (8) 4-methyl-17β-(pyrid-2-yl-amido)-4-aza-5α-androst-1-ene-3-one;-   (9) 4-methyl-17β-(pyrid-4-yl-amido)-4-aza-5α-androst-1-ene-3-one;-   (10)    4-methyl-17β-(4-(carboxymethyl)benzamido)-4-aza-5α-androst-1-ene-3-one;-   (11) 4-methyl-17β-(pyrid-3-yl-amido)-4-aza-5α-androst-1-ene-3-one;-   (12) 4-methyl-17β-(2-fluorobenzamido)-4-aza-5α-androst-1-ene-3-one;-   (13) 4-methyl-17β-(3-fluorobenzamido)-4-aza-5α-androst-1-ene-3-one;-   (14) 4-methyl-17β-(4-fluorobenzamido)-4-aza-5α-androst-1-ene-3-one;-   (15)    4-methyl-17β-(2,4-difluorobenzamido)-4-aza-5α-androst-1-ene-3-one;-   (16) 4-methyl-17β-(4-chlorobutyramido)-4-aza-5α-androst-1-ene-3-one;-   (17) 4-methyl-17β-(4-bromobutyramido)-4-aza-5α-androst-1-ene-3-one;-   (18) Carbamic acid,    [(5α,17β)-3-oxo-4-methyl-azaandrost-1-ene-17-yl]-2-bromoethyl ester;-   (19) 4-methyl-17β-(2-methylpropamido)-4-aza-5α-androst-1-ene-3-one;-   (20) 4-methyl-17β-(2-methoxyacetamido)-4-aza-5α-androst-1-ene-3-one;-   (21) 4-methyl-17β-(cyclopropamido)-4-aza-5α-androst-1-ene-3-one;-   (22) 4-methyl-17β-(acetamido)-4-aza-5α-androst-1-ene-3-one;-   (23) 4-methyl-17β-(trifluoroacetamido)-4-aza-5α-androst-1-ene-3-one;-   (24)    4-methyl-17β-(3,3,3-trifluoropropionamido)-4-aza-5α-androst-1-ene-3-one;-   (25) 4-methyl-17β-(2-cyanoacetamido)-4-aza-5α-androst-1-ene-3-one;-   (26)    4-methyl-17β-(2-methyl-2-hydroxypropamido)-4-aza-5α-androst-1-ene-3-one;-   (27) 4-methyl-17β-(thiazo-4-yl-amido)-4-aza-5α-androst-1-ene-3-one;-   (28) 4-methyl-17β-(pyrimid-2-yl-amido)-4-aza-5α-androst-1-ene-3-one;-   (29) 4-methyl-17β-(pyrimid-4-yl-amido)-4-aza-5α-androst-1-ene-3-one;-   (30) 4-methyl-17β-(oxazo-5-yl-amido)-4-aza-5α-androst-1-ene-3-one;-   (31)    4-methyl-17β-(1-methyl-imidazo-2-yl-amido)-4-aza-5α-androst-1-ene-3-one;-   (32) 4-methyl-17β-(furan-3-yl-amido)-4-aza-5α-androst-1-ene-3-one;-   (33) 4-methyl-17β-(furan-2-yl-amido)-4-aza-5α-androst-1-ene-3-one;-   (34)    4-methyl-17β-(thiophene-2-yl-amido)-4-aza-5α-androst-1-ene-3-one;-   (35)    4-methyl-17β-(thiophene-3-yl-amido)-4-aza-5α-androst-1-ene-3-one;-   (36)    4-methyl-17β-(pyridazin-2-yl-amido)-4-aza-5α-androst-1-ene-3-one;-   (37)    4-methyl-17β-(5-methyl-pyridin-2-yl-amido)-4-aza-5α-androst-1-ene-3-one;-   (38)    4-methyl-17β-(5-chloro-pyridin-2-yl-amido)-4-aza-5α-androst-1-ene-3-one;-   (39)    4-methyl-17β-(quinoline-2-yl-amido)-4-aza-5α-androst-1-ene-3-one;-   (40)    4-methyl-17β-(quinoline-8-yl-amido)-4-aza-5α-androst-1-ene-3-one;-   (41)    4-methyl-17β-(isoquinoline-8-yl-amido)-4-aza-5α-androst-1-ene-3-one;-   (42) 4-methyl-17β-(2-chlorobenzamido)-4-aza-5α-androst-1-ene-3-one;-   (43) 4-methyl-17β-(3-chlorobenzamido)-4-aza-5α-androst-1-ene-3-one;-   (44) 4-methyl-17β-(4-chlorobenzamido)-4-aza-5α-androst-1-ene-3-one;-   (45) 4-methyl-17β-(formamido)-4-aza-5α-androst-1-ene-3-one;-   (46)    4-methyl-17β-[(2-trifluoromethylphenyl)acetamido]-4-aza-5α-androst-1-ene-3-one;-   (47)    4-methyl-17β-[(4-trifluoromethylphenyl)acetamido]-4-aza-5α-androst-1-ene-3-one;-   (48)    4-methyl-17β-[(2-chlorophenyl)acetamido]-4-aza-5α-androst-1-ene-3-one;-   (49)    4-methyl-17β-[(3-chlorophenyl)acetamido]-4-aza-5α-androst-1-ene-3-one;-   (50)    4-methyl-17β-[(4-chlorophenyl)acetamido]-4-aza-5α-androst-1-ene-3-one;-   (51)    4-methyl-17β-[(2,4-dichlorophenyl)acetamido]-4-aza-5α-androst-1-ene-3-one;-   (52)    4-methyl-17β-[(3-fluorophenyl)acetamido]4-aza-5α-androst-1-ene-3-one;-   (53)    4-methyl-17β-[(4-fluorophenyl)acetamido]-4-aza-5α-androst-1-ene-3-one;-   (54)    4-methyl-17β-[(2-methoxyphenyl)acetamido]-4-aza-5α-androst-1-ene-3-one;-   (55)    4-methyl-17β-[(3-methoxyphenyl)acetamido]-4-aza-5α-androst-1-ene-3-one;-   (56)    4-methyl-17β-[(2,5-dimethoxyphenyl)acetamido]-4-aza-5α-androst-1-ene-3-one;-   (57)    4-methyl-17β-[(3,5-difluorophenyl)acetamido]-4-aza-5α-androst-1-ene-3-one;-   (58)    4-methyl-17β-[(3-nitrophenyl)acetamido]-4-aza-5α-androst-1-ene-3-one;-   (59)    4-methyl-17β-(tetrahydrofuran-2-yl-amido)-4-aza-5α-androst-1-ene-3-one;-   (60)    4-methyl-17β-(tetrahydrofuran-3-yl-amido)-4-aza-5α-androst-1-ene-3-one;-   (61)    4-methyl-17β-(4-ethyl-pyridin-2-yl-amido)-4-aza-5α-androst-1-ene-3-one;-   (62)    4-methyl-17β-(3-methyl-pyridin-2-yl-amido)4-aza-5α-androst-1-ene-3-one;-   (63)    4-methyl-17β-(3-bromo-pyridin-2-yl-amido)-4-aza-5α-androst-1-ene-3-one;-   (64)    4-methyl-17β-(4-bromo-pyridin-2-yl-amido)-4-aza-5α-androst-1-ene-3-one;-   (65)    4-methyl-17β-[(2-phenylcyclopropyl)amido]-4-aza-5α-androst-1-ene-3-one;-   (66)    4-methyl-17β-[(2-fluorophenyl)acetamido]-4-aza-5α-androst-1-ene-3-one;-   (67)    4-methyl-17β-[(pyrid-2-yl)acetamido]-4-aza-5α-androst-1-ene-3-one;-   (68)    4-methyl-17β-[(pyrid-3-yl)acetamido]-4-aza-5α-androst-1-ene-3-one;-   (69)    4-methyl-17β-[(4-methoxyphenyl)acetamido]-4-aza-5α-androst-1-ene-3-one;-   (70)    4-methyl-17β-[3-(2-fluorophenyl)propionamido]-4-aza-5α-androst-1-ene-3-one;-   (71)    4-methyl-17β-[3-(4-fluorophenyl)propionamido]-4-aza-5α-androst-1-ene-3-one;-   (72)    4-methyl-17β-[3-(4-rifluoromethylphenyl)propionamido]-4-aza-5α-androst-1-ene-3-one;-   (73)    4-methyl-17β-[3-(2-chlorophenyl)propionamido]-4-aza-5α-androst-1-ene-3-one;-   (74)    4-methyl-17β-[3-(3-chlorophenyl)propionamido]-4-aza-5α-androst-1-ene-3-one;-   (75)    4-methyl-17β-[3-(4-chlorophenyl)propionamido]-4-aza-5α-androst-1-ene-3-one;-   (76)    4-methyl-17β-[2-trifluoromethylcinnamido]-4-aza-5α-androst-1-ene-3-one;-   (77) 4-methyl-17β-[2-chlorocinnamido]-4-aza-5α-androst-1-ene-3-one;-   (78) 4-methyl-17β-[2-fluorocinnamido]-4-aza-5α-androst-1-ene-3-one;-   (79)    4-methyl-17β-[4-(2,5-dichlorophenyl)butanamido]-4-aza-5α-androst-1-ene-3-one;-   (80)    4-methyl-17β-[4-(2-nitrophenyl)butanamido]-4-aza-5α-androst-1-ene-3-one;-   (81)    4-methyl-17β-[4-(3,4-dimethoxyphenyl)butanamido]-4-aza-5α-androst-1-ene-3-one;-   (82) 4-methyl-17β-[propionamido]-4-aza-5α-androst-1-ene-3-one;-   (83) 4-methyl-17β-[butyramido]-4-aza-5α-androst-1-ene-3-one;-   (84)    4-methyl-17β-[(2-methyl)cyclopropamido]-4-aza-5α-androst-1-ene-3-one;-   (85) Carbamic acid,    [(5α,17β)-3-oxo-4-methyl-azaandrost-1-ene-17-yl]-phenyl ester;-   (86) Carbamic acid,    [(5α,17β)-3-oxo-4-methyl-azaandrost-1-ene-17-yl]4-chlorophenyl    ester;-   (87) Carbamic acid,    [(5α,17β)-3-oxo-4-methyl-azaandrost-1-ene-17-yl]4-nitrophenyl ester;-   (88) Carbamic acid,    [(5α,17β)-3-oxo-4-methyl-azaandrost-1-ene-17-yl]-4-methylphenyl    ester;-   (89) Carbamic acid,    [(5α,17β)-3-oxo-4-methyl-azaandrost-1-ene-17-yl]4-bromophenyl ester;-   (90) Carbamic acid,    [(5α,17β)-3-oxo-4-methyl-azaandrost-1-ene-17-yl]-4-fluorophenyl    ester;-   (91) Carbamic acid,    [(5α,17β)-3-oxo-4-methyl-azaandrost-1-ene-17-yl]-4-methoxophenyl    ester;-   (92) Carbamic acid,    [(5α,17β)-3-oxo-4-methyl-azaandrost-1-ene-17-yl]-2-nitrophenyl    ester;-   (93) Carbamic acid,    [(5α,17β)-3-oxo-4-methyl-azaandrost-1-ene-17-yl]-3-naphthyl ester;-   (94) Carbamic acid,    [(5α,17β)-3-oxo-4-methyl-azaarndrost-1-ene-17-yl]-3-trifluoromethylphenyl    ester;-   (95) Carbamic acid,    [(5α,17β)-3-oxo-4-methyl-azaandrost-1-ene-17-yl]-ethyl ester;-   (96) Carbamic acid,    [(5α,17β)-3-oxo-4-methyl-azaandrost-1-ene-17-yl]-benzyl ester;-   (97) Carbamic acid,    [(5α,17β)-3-oxo-4-methyl-azaandrost-1-ene-17-yl]-2,2,2-trifluoroethyl    ester;-   (98) Carbamic acid,    [(5α,17β)-3-oxo-4-methyl-azaandrost-1-ene-17-yl]-2-methoxyethyl    ester;-   (99) Carbamic acid,    [(5α,17β)-3-oxo-4-methyl-azaandrost-1-ene-17-yl]-(2,2-dimethylpropy)    ester;-   (100) Carbamic acid,    [(5α,17β)-3-oxo-4-methyl-azaandrost-1-ene-17-yl]-2-fluoroethyl    ester;-   (101) Carbamic acid,    [(5α,17β)-3-oxo-4-methyl-azaandrost-1-ene-17-yl]-allyl ester;-   (102) Carbamic acid,    [(5α,17β)-(3)-3-oxo-4-methyl-azaandrost-1-ene-17-yl]-methyl ester;-   (103) Carbamic acid,    [(5α,17β)-3-oxo-4-methyl-azaandrost-1-ene-17-yl]-1-propynoic ester;-   (104) Carbamic acid,    [(5α,17β)-3-oxo-4-methyl-azaandrost-1-ene-17-yl]-(2-methyl-2-butyl)    ester;-   (105) Carbamic acid,    [(5α,17β)-3-oxo-4-methyl-azaandrost-1-ene-17-yl]-2-(trifluoromethyl)phenyl    ester;-   (106) Carbamic acid,    [(5α,17β)-3-oxo-4-methyl-azaandrost-1-ene-17-yl]-4-(trifluoromethyl)phenyl    ester;-   (107) Carbamic acid,    [(5α,17β)-3-oxo-4-methyl-azaandrost-1-ene-17-yl]-2-fluorophenyl    ester;-   (108) Carbamic acid,    [(5α,17β)-3-oxo-4-methyl-azaandrost-1-ene-17-yl]-3-fluorophenyl    ester;-   (109) Carbamic acid,    [(5α,17β)-3-oxo-4methyl-azaandrost-1-ene-17-yl]-(2-hydroxy-1-ethyl)    ester;-   (110) Carbamic acid,    [(5α,17β)-3-oxo-4-methyl-azaandrost-1-ene-17-yl]-2-methoxyphenyl    ester;-   (111) Carbamic acid,    [(5α,17β)-3-oxo-4-methyl-azaandrost-1-ene-17-yl]-3-methoxyphenyl    ester;-   (112) Carbamic acid,    [(5α,17β)-3-oxo-4-methyl-azaandrost-1-ene-17-yl]-2-ethoxyphenyl    ester;-   (113) Carbamic acid,    [(5α,17α)-3-oxo-4-methyl-azaandrost-1-ene-17-yl]-3-ethoxyphenyl    ester;-   (114) Carbamic acid,    [(5α,17β)-3-oxo-4-methyl-azaandrost-1-ene-17-yl]-4-ethoxyphenyl    ester;-   (115) Carbamic acid,    [(5α,17β)-3-oxo-4-methyl-azaandrost-1-ene-17-yl]-4-chlorophenyl    ester;-   (116) Carbamic acid,    [(5α,17β)-3-oxo-4-methyl-azaandrost-1-ene-17-yl]-3-chlorophenyl    ester;-   (117) Carbamic acid,    [(5α,17β)-3-oxo-4-methyl-azaandrost-1-ene-17-yl]-3-(trifluoromethoxy)phenyl    ester;-   (118) Carbamic acid,    [(5α,17β)-3-oxo-4-methyl-azaandrost-1-ene-17-yl]-4-(trifluoromethoxy)phenyl    ester;-   (119) Carbamic acid,    [(5α,17β)-3-oxo-4-methyl-azaandrost-1-ene-17-yl]-2-propyl ester;-   (120) Carbamic acid,    [(5α,17β)-3-oxo-4-methyl-azaandrost-1-ene-17-yl]-1-propyl ester;-   (121) Carbamic acid,    [(5α,17β)-3-oxo-4-methyl-azaandrost-1-ene-17-yl]-1-butyl ester;-   (122) Carbamic acid,    [(5α,17β)-3-oxo-4-methyl-azaandrost-1-ene-17-yl]-1-hexyl ester;-   (123) 4-methyl-17β-(phenylsulfonamido)-4-aza-5α-androst-1-ene-3-one;-   (124)    4-methyl-17β-(2-trifluoromethylphenylsulfonamido)-4-aza-5α-androst-1-ene-3-one;-   (125)    4-methyl-17β-(3-trifluoromethylphenylsulfonamido)-4-aza-5α-androst-1-ene-3-one;-   (126)    4-methyl-17β-(2-chlorophenylsulfonamido)-4-aza-5α-androst-1-ene-3-one;-   (127)    4-methyl-17β-(3-chlorophenylsulfonamido)-4-aza-5α-androst-1-ene-3-one;-   (128)    4-methyl-17β-(2-trifluoromethoxyphenylsulfonamido)-4-aza-5α-androst-1-ene-3-one;-   (129)    4-methyl-17β-(2-cyanophenylsulfonamido)-4-aza-5α-androst-1-ene-3-one;-   (130)    4-methyl-17β-(4-methoxyphenylsulfonamido)-4-aza-5α-androst-1-ene-3-one;-   (131)    4-methyl-17β-(3-bromo-5-methoxyphenylsulfonamido)-4-aza-5α-androst-1-ene-3-one;-   (132)    4-methyl-17β-(8-quinolylsulfonamido)-4-aza-5α-androst-1-ene-3-one;-   (133)    4-methyl-17β-(3-cyanophenylsulfonamido)-4-aza-5α-androst-1-ene-3-one;-   (134)    4-methyl-17β-(4-chlorophenylsulfonamido)-4-aza-5α-androst-1-ene-3-one;-   (135)    4-methyl-17β-[(2-methylsufonyl)phenyl]sulfonamido)-4-aza-5α-androst-1-ene-3-one;-   (136) N-[(5α,17β)-4-methyl-3-oxo-4-azaandrost-1-en-17-yl]-N′-phenyl    urea;-   (137)    N-[(5α,17β)-4-methyl-3-oxo-4-azaandrost-1-en-17-yl]-N′-(2-trifluoromethyl)phenyl    urea;-   (138)    N-[(5α,17β)-4-methyl-3-oxo-4-azaandrost-1-en-17-yl]-N′-(3-trifluoromethyl)phenyl    urea;-   (139)    N-[(5α,17β)-4-methyl-3-oxo-4-azaandrost-1-en-17-yl]-N′-3-chlorophenyl    urea;-   (140)    N-[(5α,17β)-4-methyl-3-oxo-4-azaandrost-1-en-17-yl]-N′-(4-chloro-2-trifluoromethylphenyl)urea;-   (141)    N-[(5αa,17β)-4-methyl-3-oxo-4-azaandrost-1-en-17-yl]-N′-3-acetylphenyl    urea;-   (142)    N-[(5α,17β)-4-methyl-3-oxo-4-azaandrost-1-en-17-yl]-N′-(5-chloro-2-trifluoromethylphenyl)urea;-   (143)    N-[(5α,17β)-4-methyl-3-oxo-4-azaandrost-1-en-17-yl]-N′-(2,4-[bistrifluoromethyl]phenyl)urea;-   (144)    N-[(5α,17β)-4-methyl-3-oxo-4-azaandrost-1-en-17-yl]-N′-(3,4-difluorophenyl)urea;-   (145)    N-[(5α,17β)-4-methyl-3-oxo-4-azaandrost-1-en-17-yl]-N′-(2,3-dichlorophenyl)urea;-   (146)    N-[(5α,17β)-4-methyl-3-oxo-4-azaandrost-1-en-17-yl]-N′-(2,4-dichlorophenyl)urea;-   (147)    N-[(5α,17β)-4-methyl-3-oxo-4-azaandrost-1-en-17-yl]-N′-(3,4-dichlorophenyl)urea;-   (148)    N-[(5α,17β)-4-methyl-3-oxo-4-azaandrost-1-en-17-yl]-N′-2-chlorophenyl)urea;-   (149)    N-[(5α,17β)-4-methyl-3-oxo-4-azaandrost-1-en-17-yl]-N′-(2-chloro-5-trifluoromethylphenyl)urea;-   (150)    N-[(5α,17β)-4-methyl-3-oxo-4-azaandrost-1-en-17-yl]-N′-(4-chloro-3-trifluoromethylphenyl)urea;-   (151)    N-[(5α,17β)-4-methyl-3-oxo-4-azaandrost-1-en-17-yl]-N′-(4-trifluoromethyl)phenyl    urea;-   (152)    N-[(5α,17β)-4-methyl-3-oxo-4-azaandrost-1-en-17-yl]-N′-(2,3-dimethylpheny)urea;-   (153) N-[(5α,17β)-4-methyl-3-oxo-4-azaandrost-1-en-17-yl]-N′-methyl    urea;-   (154) N-[(5α,17β)-4-methyl-3-oxo-4-azaandrost-1-en-17-yl]-N′-ethyl    urea;-   (155)    N-[(5α,17β)-4-methyl-3-oxo-4-azaandrost-1-en-17-yl]-N′-dimethyl    urea;-   (156) N-[(5α,17β)-4-methyl-3-oxo-4-azaandrost-1-en-17-yl]-N′-diethyl    urea;-   (157) N-[(5α,17β)-4-methyl-3-oxo-4-azaandrost-1-en-17-yl] urea;

The term “alkyl” shall mean straight or branched chain alkanes of one toten total carbon atoms, or any number within this range (i.e., methyl,ethyl, 1-propyl, 2-propyl, n-butyl, s-butyl, t-butyl, etc.). The term“C₀ alkyl” (as in “C₀₋₈ alkylaryl”) shall refer to the absence of analkyl group.

The term “alkenyl” shall mean straight or branched chain alkenes of twoto ten total carbon atoms, or any number within this range.

The term “alkynyl” shall mean straight or branched chain alkynes of twoto ten total carbon atoms, or any number within this range.

The term “cycloalkyl” shall mean cyclic rings of alkanes of three toeight total carbon atoms, or any number within this range (i.e.,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl orcyclooctyl).

The term “cycloheteroalkyl,” as used herein, shall mean a 3- to8-membered fully saturated heterocyclic ring containing one or twoheteroatoms chosen from N, O, or S and optionally fused to another fullysaturated ring. Examples of cycloheteroalkyl groups include, but are notlimited to piperidinyl, pyrrolidinyl, azetidinyl, morpholinyl,piperazinyl, tetrahydrofuranyl, and octahydroquinolizinyl. In oneembodiment of the present invention cycloheteroalkyl is selected frompiperidinyl, pyrrolidinyl, tetrahydrofuranyl, and morpholinyl.

The term “alkoxy,” as used herein, refers to straight or branched chainalkoxides of the number of carbon atoms specified (e.g., C₁₋₅ alkoxy),or any number within this range (i.e., methoxy, ethoxy, etc.).

The term “aryl,” as used herein, refers to a monocyclic or bicyclicsystem comprising at least one aromatic ring, wherein the monocylic orbicyclic system contains 0, 1, 2, 3, or 4 heteroatoms chosen from N, O,or S, and wherein the monocylic or bicylic system is eitherunsubstituted or substituted with one or more groups independentlyselected from hydrogen, halogen, aryl, C₁₋₈ alkyl, C₃₋₈ cycloalkyl, C₃₋₈cycloheteroalkyl, aryl C₁₋₆alkyl, amino C₀₋₆alkyl, C₁₋₆ alkylaminoC₀₋₆alkyl, (C₁₋₆ alkyl)₂amino C₀₋₆alkyl, aryl C₀₋₆ alkylamino C₀₋₆alkyl,(aryl C₀₋₆ alkyl)₂amino C₀₋₆alkyl, C₁₋₆ alkylthio, aryl C₀₋₆alkylthio,C₁₋₆ alkylsulfinyl, aryl C₀₋₆alkylsulfinyl, C₁₋₆ alkylsulfonyl, arylC₀₋₆alkylsulfonyl, C₁₋₆ alkoxy C₀₋₆alkyl, aryl C₀₋₆ alkoxy C₀₋₆alkyl,hydroxycarbonyl C₀₋₆alkyl, C₁₋₆ alkoxycarbonyl C₀₋₆alkyl, aryl C₀₋₆alkoxycarbonyl C₀₋₆alkyl, hydroxycarbonyl C₁₋₆ alkyloxy, hydroxyC₀₋₆alkyl, cyano, nitro, perfluoroC₁₋₄alkyl, perfluoroC₁₋₄alkoxy, oxo,C₁₋₆ alkylcarbonyloxy, aryl C₀₋₆alkylcarbonyloxy, C₁₋₆alkylcarbonylamino, aryl C₀₋₆ alkylcarbonylamino, C₁₋₆alkylsulfonylamino, aryl C₀₋₆alkylsulfonylamino, C₁₋₆alkoxycarbonylamino, aryl C₀₋₆ alkoxycarbonylamino,C₁₋₆alkylaminocarbonylamino, aryl C₀₋₆alkylaminocarbonylamino,(C₁₋₆alkyl)₂ aminocarbonylamino, (aryl C₀₋₆alkyl)₂ aminocarbonylamino,(C₁₋₆alkyl)₂ aminocarbonyloxy, (aryl C₀₋₆alkyl)₂ aminocarbonyloxy, andC₀₋₆alkylcarbonyl C₀₋₆ alkyl. Examples of aryl include, but are notlimited to, phenyl, naphthyl, pyridyl, pyrrolyl, pyrazolyl, pyrazinyl,pyrimidinyl, imidazolyl, benzimidazolyl, benzthiazolyl, benzoxazolyl,indolyl, thiophenyl, furanyl, dihydrobenzofuranyl, benzo(1,3)dioxolanyl,benzo(1,4)dioxanyl, oxazolyl, isoxazolyl, thiazolyl, quinolinyl,isothiazolyl, indanyl, isoquinolinyl, dihydroisoquinolinyl,tetrahydronaphthyridinyl, benzothienyl, imidazopyridinyl,tetrahydrobenzazepinyl, quinoxalinyl, imidazopyrimidinyl,cyclopentenopyridinyl, phthalazinyl, tetrahydroquinolinyl, oxindolyl,isoquinolinyl, imidazothiazolyl, dihydroimidazothiazolyl, tetrazolyl,triazolyl, pyridazinyl, piperidinyl, piperazinyl, oxadiazolyl,thiadiazolyl, triazinyl, indazolyl, indazolinone, dihydrobenzofuranyl,phthalide, phthalimide, coumarin, chromone, tetrahydroisoquindine,naphthyridinyl, tetrahydronaphthyridinyl, isoindolinyl,triazanaphthalinyl, pteridinyl, and purinyl, which are eitherunsubstituted or substituted with one or more groups independentlyselected from hydrogen, halogen, aryl, C₁₋₈ alkyl, C₃₋₈ cycloalkyl, C₃₋₈cycloheteroalkyl, aryl C₁₋₆alkyl, amino C₀₋₆alkyl, C₁₋₆ alkylaminoC₀₋₆alkyl, (C₁₋₆ alkyl)₂amino C₀₋₆alkyl, aryl C₀₋₆ alkylamino C₀₋₆alkyl,(aryl C₀₋₆ alkyl)₂amino C₀₋₆alkyl, C₁₋₆ alkylthio, aryl C₀₋₆alkylthio,C₁₋₆ alkylsulfinyl, aryl C₀₋₆alkylsulfinyl, C₁₋₆ alkylsulfonyl, arylC₀₋₆alkylsulfonyl, C₁₋₆ alkoxy C₀₋₆alkyl, aryl C₀₋₆ alkoxy C₀₋₆alkyl,hydroxycarbonyl C₀₋₆alkyl, C₁₋₆ alkoxycarbonyl C₀₋₆alkyl, aryl C₀₋₆alkoxycarbonyl C₀₋₆alkyl, hydroxycarbonyl C₁₋₆ alkyloxy, hydroxyC₀₋₆alkyl, cyano, nitro, perfluoroC₁₋₄alkyl, perfluoroC₁₋₄alkoxy, oxo,C₁₋₆ alkylcarbonyloxy, aryl C₀₋₆alkylcarbonyloxy, C₁₋₆alkylcarbonylamino, aryl C₀₋₆ alkylcarbonylamino, C₁₋₆alkylsulfonylamino, aryl C₀₋₆alkylsulfonylamino, C₁₋₆alkoxycarbonylamino, aryl C₀₋₆ alkoxycarbonylamino,C₁₋₆alkylaminocarbonylamino, aryl C₀₋₆alkylaminocarbonylamino,(C₁₋₆alkyl)₂ aminocarbonylamino, (aryl C₀₋₆alkyl)₂ aminocarbonylamino,(C₁₋₆alkyl)₂ aminocarbonyloxy, (aryl C₀₋₆alkyl)₂ aminocarbonyloxy, andC₀₋₆alkylcarbonyl C₀₋₆alkyl. In one embodiment of the present invention,aryl is selected from phenyl, pyridyl, pyrazolyl, benzamidazolyl,imidazolyl, furanyl, napthyl, indolyl, indanyl, thiophenyl, pyrazinyl,benzothienyl, 3,4dihydro-1(1H)-isoquinolinyl,1-8-tetrahydronaphthyridinyl, imidazo[1,2-a]pyridinyl,2-oxo-2,3,4,5-tetrahydro-1H-benzo[B]azepinyl, quinoxalinyl,imidazo[1,2-a]pyrimidinyl, 2-3-cyclopentenopyridinyl,1-(2H)-phthalazinyl, 1,2,3,4-tetrahydroquinolinyl, oxindolyl,isoquinolinyl, imidazo[2,1-b][1,3]thiazolyl,2,3-dihydroimidazo[2,1-b][1,3]thiazolyl, and quinolinyl. Preferably, thearyl group is unsubstituted, mono-, di-, or tri-substituted with one tothree of the above-named substituents; more preferably, the aryl groupis unsubstituted, mono- or di-substituted with one to two of theabove-named substituents.

Whenever the term “alkyl” or “aryl” or either of their prefix rootsappears in a name of a substituent (e.g., aryl C₀₋₈ alkyl), it shall beinterpreted as including those limitations given above for “alkyl” and“aryl.” Designated numbers of carbon atoms (e.g., C₀₋₈) shall referindependently to the number of carbon atoms in an alkyl or cyclic alkylmoiety or to the alkyl portion of a larger substituent in which alkylappears as its prefix root.

The terms “arylalkyl” and “alkylaryl” include an alkyl portion wherealkyl is as defined above and to include an aryl portion where aryl isas defined above. Examples of arylalkyl include, but are not limited to,benzyl, fluorobenzyl, chlorobenzyl, phenylethyl, phenylpropyl,fluorophenylethyl, chlorophenylethyl, methyl, thiophenylethyl, andthiophenylpropyl. Examples of alkylaryl include, but are not limited to,toluene, ethylbenzene, propylbenzene, methylpyridine, ethylpyridine,propylpyridine and butylpyridine.

The term “halogen” shall include iodine, bromine, chlorine, andfluorine.

The term “oxy” means an oxygen (O) atom. The term “thio” means a sulfur(S) atom. The term “oxo” means “═O”. The term “carbonyl” means “C═O.”

The term “substituted” shall be deemed to include multiple degrees ofsubstitution by a named substitutent. Where multiple substituentmoieties are disclosed or claimed, the substituted compound can beindependently substituted by one or more of the disclosed or claimedsubstituent moieties, singly or plurally. By independently substituted,it is meant that the (two or more) substituents can be the same ordifferent.

When any variable (e.g., R³, R⁴, etc.) occurs more than one time in anyconstituent or in formula I, its definition on each occurrence isindependent of its definition at every other occurrence. Also,combinations of substituents and/or variables are permissible only ifsuch combinations result in stable compounds.

Under standard nomenclature used throughout this disclosure, theterminal portion of the designated side chain is described first,followed by the adjacent functionality toward the point of attachment.For example, a C₁₋₅ alkylcarbonylamino C₁₋₆ alkyl substituent isequivalent to

In choosing compounds of the present invention, one of ordinary skill inthe art will recognize that the various substituents, i.e. R¹, R², R³,etc., are to be chosen in conformity with well-known principles ofchemical structure connectivity.

The term “substituted” shall be deemed to include multiple degrees ofsubstitution by a named substitutent. Where multiple substituentmoieties are disclosed or claimed, the substituted compound can beindependently substituted by one or more of the disclosed or claimedsubstituent moieties, singly or plurally. By independently substituted,it is meant that the (two or more) substituents can be the same ordifferent.

Representative compounds of the present invention typically displaysubmicromolar affinity for the androgen receptor. Compounds of thisinvention are therefore useful in treating mammals suffering fromdisorders related to androgen receptor function. Pharmacologicallyeffective amounts of the compound, including the pharmaceuticallyeffective salts thereof, are administered to the mammal, to treatdisorders related to androgen receptor function, or which can beimproved by the addition of additional androgen, such as osteoporosis,osteopenia, glucocorticoid-induced osteoporosis, periodontal disease,HIV-wasting, cancer cachexia, bone fracture, bone damage following bonereconstructive surgery, muscular dystrophies, sarcopenia, frailty, agingskin, male hypogonadism, post-menopausal symptoms in women, femalesexual dysfunction, premature ovarian failure, autoimmune disease,atherosclerosis, hypercholesterolemia, hyperlipidemia, aplastic anemiaand other hematopoietic disorders, pancreatic cancer, renal cancer,arthritis and joint repair. Still further, the compounds of the presentinvention are useful in treating insulin resistence, including NIDDM,obesity and growth retardation associated with obesity,hyperinsulinemia, as well as Metabolic Syndrome, or “Syndrome X” asdefined in Johannsson, J. Clin Endocrin. Metabl 82: 727-34 (1997).

It is generally preferable to administer compounds of the presentinvention as enantiomerically pure formulations. Racemic mixtures can beseparated into their individual enantiomers by any of a number ofconventional methods. These include chiral chromatography,derivatization with a chiral auxiliary followed by separation bychromatography or crystallization, and fractional crystallization ofdiastereomeric salts.

As used herein, a compound that binds to an intracellular receptor, suchas the androgen receptor, and mimics the effect of the natural ligand isreferred to as an “agonist”; whereas, a compound that inhibits theeffect of the natural ligand is called an “antagonist.” The term “tissueselective androgen receptor modulator” refers to to an androgen receptorligand that mimics the action of the natural ligand in some tissues butnot in others.

Compounds according to the present invention may be prepared accordingto the procedures outlined in Scheme A and as detailed in the Examples.

Following procedures described by Rasmusson et al. (J. Med. Chem., 1986,29, 2298-2315), the keto-acid II may be reacted with an amine in asolvent such as ethylene glycol at elevated temperature to producecompounds of structure III. When ammonia is used as the amine theproduct is an unsubstituted lactam. In this case (III, R¹═H), thenitrogen may then be alkylated by treatment of the lactam with a basesuch as sodium hydride in an aprotic solvent (e.g. tetrahydrofuran,“THF”) followed by reaction with an appropriate electrophile.4-Azasteroids of structure IV may be obtained by reduction of the5,6-double bond of III using hydrogen gas and a catalyst such aspalladium on carbon in an organic solvent. Such solvents include ethylacetate, ethanol and methanol. Alternatively, the 5,6-double bond may besaturated using a reducing agent such as sodium cyanoborohydride in thepresence of an acid, for example trifluoroacetic acid, in a suitableorganic solvent. A second route to compounds of structure IV involvesthe catalytic reduction of the 1,2-double bond of V.

The preparation of 4-azasteroids of general structure V involves thedehydrogenation of compound IV. Methods to achieve this are described inU.S. Pat. No. 5,302,621. Similarly, the introduction of a 1,2-doublebond into III will yield the 1,2 and 5,6-unsaturated 4-aza steroids VI.Such methods include dehydrogenation using2,3-dichloro-5,6-dicyano-p-benzoquinone in the presence of a silylatingagent. A second method requires the treatment of IV (or III) withbenzeneseleninic anhydride in an inert solvent at elevated temperature.Alternatively, reaction of IV (or III) with a base such as diisopropyllithium amide followed by treatment with a diaryl sulfide allows theintroduction of a 2-arylthioether. This 2-arylthioether may then beoxidized (e.g. with a peracid) to produce a sulfoxide which is theneliminated to yield V (or VI). 4-Unsubstituted 4-azasteroids (III-VI)can be alkylated on nitrogen to produce 4-substituted 4-azasteroids.This transformation can be accomplished using a base such as sodiumhydride in an aprotic solvent (e.g., THF) followed by reaction with anelectrophile such as an alkylbromide or alkyliodide.

Formation of the C-17 amide bond to give VIII is readily achieved fromthe corresponding acid VII by activation of the acid and then reactionwith the required amine (U.S. Pat. No. 5,302,621). Methods used toactivate the acid include treatment with 1,2-dichloroethane “EDC” and1-hydroxybenzotriazole “HOBT” (or 1-hydroxy-7-azabenzotriazole “HOAT”)in a solvent such as dimethylformamide “DMF”. A second method involvesthe formation of a thiopyridylester followed by displacement with anamine which may be aided by the presence of silver salts (e.g. silvertriflate). A third method requires the formation of the acid chloridefrom the acid. A fourth method involves the use of carbonyldiimidazoleto generate the imidazolide intermediate (U.S. Pat. No. 5,237,061).Reaction of this with a substituted amino magnesium regent thengenerates the desired C-17 amide. Additionally, it is possible to form amixed anhydride and then use this to generate the amide by methodsreadily appreciated by one of ordinary skill in the art.

The term “pharmaceutically acceptable salt” is intended to include allacceptable salts such as acetate, lactobionate, benzenesulfonate,laurate, benzoate, malate, bicarbonate, maleate, bisulfate, mandelate,bitartrate, mesylate, borate, methylbromide, bromide, methylnitrate,calcium edetate, methylsulfate, camsylate, mucate, carbonate, napsylate,chloride, nitrate, clavulanate, N-methylglucamine, citrate, ammoniumsalt, dihydrochloride, oleate, edetate, oxalate, edisylate, pamoate(embonate), estolate, palmitate, esylate, pantothenate, fulmarate,phosphate/diphosphate, gluceptate, polygalacturonate, gluconate,salicylate, glutamate, stearate, glycollylarsanilate, sulfate,hexylresorcinate, subacetate, hydrabamine, succinate, hydrobromide,tannate, hydrochloride, tartrate, hydroxynaphthoate, teoclate, iodide,tosylate, isothionate, triethiodide, lactate, panoate, valerate, and thelike which can be used as a dosage form for modifying the solubility orhydrolysis characteristics or can be used in sustained release orpro-drug formulations.

The term “therapeutically effective amount” means the amount thecompound of structural formula I that will elicit the biological ormedical response of a tissue, system, animal or human that is beingsought by the researcher, veterinarian, medical doctor or otherclinician.

The term “composition” as used herein is intended to encompass a productcomprising the specified ingredients in the specified amounts, as wellas any product which results, directly or indirectly, from combinationof the specified ingredients in the specified amounts.

By “pharmaceutically acceptable” it is meant the carrier, diluent orexcipient must be compatible with the other ingredients of theformulation and not deleterious to the recipient thereof.

The terms “administration of” and or “administering a” compound shouldbe understood to mean providing a compound of the invention or a prodrugof a compound of the invention to the individual in need of treatment.

The administration of the compound of structural formula I in order topractice the present methods of therapy is carried out by administeringan effective amount of the compound of structural formula I to thepatient in need of such treatment or prophylaxis. The need for aprophylactic administration according to the methods of the presentinvention is determined via the use of well known risk factors. Theeffective amount of an individual compound is determined, in the finalanalysis, by the physician in charge of the case, but depends on factorssuch as the exact disease to be treated, the severity of the disease andother diseases or conditions from which the patient suffers, the chosenroute of administration other drugs and treatments which the patient mayconcomitantly require, and other factors in the physician's judgment.

Generally, the daily dosage of the compound of structural formula I maybe varied over a wide range from 0.01 to 1000 mg per adult human perday. Most preferably, dosages range from 0.1 to 200 mg/day. For oraladministration, the compositions are preferably provided in the form oftablets containing 0.01 to 1000 mg, particularly 0.01, 0.05, 0.1, 0.5,1.0, 2.5, 3.0, 5.0, 6.0, 10.0, 15.0, 25.0, 50.0, 75, 100, 125, 150, 175,180, 200, 225, and 500 milligrams of the active ingredient for thesymptomatic adjustment of the dosage to the patient to be treated.

The dose may be administered in a single daily dose or the total dailydosage may be administered in divided doses of two, three or four timesdaily. Furthermore, based on the properties of the individual compoundselected for administration, the dose may be administered lessfrequently, e.g., weekly, twice weekly, monthly, etc. The unit dosagewill, of course, be correspondingly larger for the less frequentadministration.

When administered via intranasal routes, transdermal routes, by rectalor vaginal suppositories, or through a continual intravenous solution,the dosage administration will, of course, be continuous rather thanintermittent throughout the dosage regimen.

Exemplifying the invention is a pharmaceutical composition comprisingany of the compounds described above and a pharmaceutically acceptablecarrier. Also exemplifying the invention is a pharmaceutical compositionmade by combining any of the compounds described above and apharmaceutically acceptable carrier. An illustration of the invention isa process for making a pharmaceutical composition comprising combiningany of the compounds described above and a pharmaceutically acceptablecarrier.

Formulations of the tissue selective androgen receptor modulatoremployed in the present method for medical use comprise the compound ofstructural formula I together with an acceptable carrier thereof andoptionally other therapeutically active ingredients. The carrier must bepharmaceutically acceptable in the sense of being compatible with theother ingredients of the formulation and not deleterious to therecipient subject of the formulation.

The present invention, therefore, further provides a pharmaceuticalformulation comprising the compound of structural formula I togetherwith a pharmaceutically acceptable carrier thereof.

The formulations include those suitable for oral, rectal, intravaginal,topical or parenteral (including subcutaneous, intramuscular andintravenous administration). Preferred are those suitable for oraladministration.

The formulations may be presented in a unit dosage form and may beprepared by any of the methods known in the art of pharmacy. All methodsinclude the step of bringing the active compound in association with acarrier which constitutes one or more ingredients. In general, theformulations are prepared by uniformly and intimately bringing theactive compound in association with a liquid carrier, a waxy solidcarrier or a finely divided solid carrier, and then, if needed, shapingthe product into desired dosage form.

Formulations of the present invention suitable for oral administrationmay be presented as discrete units such as capsules, cachets, tablets orlozenges, each containing a predetermined amount of the active compound;as a powder or granules; or a suspension or solution in an aqueousliquid or non-aqueous liquid, e.g., a syrup, an elixir, or an emulsion.

A tablet may be made by compression or molding, optionally with one ormore accessory ingredients. Compressed tablets may be prepared bycompressing in a suitable machine the active compound in a free flowingform, e.g., a powder or granules, optionally mixed with accessoryingredients, e.g., binders, lubricants, inert diluents, disintegratingagents or coloring agents. Molded tablets may be made by molding in asuitable machine a mixture of the active compound, preferably inpowdered form, with a suitable carrier. Suitable binders include,without limitation, starch, gelatin, natural sugars such as glucose orbeta-lactose, corn sweeteners, natural and synthetic gums such asacacia, tragacanth or sodium alginate, carboxymethyl-cellulose,polyethylene glycol, waxes and the like. Lubricants used in these dosageforms include, without limitation, sodium oleate, sodium stearate,magnesium stearate, sodium benzoate, sodium acetate, sodium chloride andthe like. Disintegrators include, without limitation, starch, methylcellulose, agar, bentonite, xanthan gum and the like.

Oral liquid forms, such as syrups or suspensions in suitably flavoredsuspending or dispersing agents such as the synthetic and natural gums,for example, tragacanth, acacia, methyl cellulose and the like may bemade by adding the active compound to the solution or suspension.Additional dispersing agents which may be employed include glycerin andthe like.

Formulations for vaginal or rectal administration may be presented as asuppository with a conventional carrier, i.e., a base that is nontoxicand nonirritating to, mucous membranes, compatible with the compound ofstructural formula I, and is stable in storage and does not bind orinterfere with the release of the compound of structural formula I.Suitable bases include: cocoa butter (theobroma oil), polyethyleneglycols (such as carbowax and polyglycols), glycol-surfactantcombinations, polyoxyl 40 stearate, polyoxyethylene sorbitan fatty acidesters (such as Tween, Myrj, and Arlacel), glycerinated gelatin, andhydrogenated vegetable oils. When glycerinated gelatin suppositories areused, a preservative such as methylparaben or propylparaben may beemployed.

Topical preparations containing the active drug component can be admixedwith a variety of carrier materials well known in the art, such as,e.g., alcohols, aloe vera gel, allantoin, glycerine, vitamin A and Eoils, mineral oil, PPG2 myristyl propionate, and the like, to form,e.g., alcoholic solutions, topical cleansers, cleansing creams, skingels, skin lotions, and shampoos in cream or gel formulations.

The compounds of the present invention can also be administered in theform of liposome delivery systems, such as small unilamellar vesicles,large unilamellar vesicles and multilamellar vesicles. Liposomes can beformed from a variety of phospholipids, such as cholesterol,stearylamine or phosphatidylcholines.

Compounds of the present invention may also be delivered by the use ofmonoclonal antibodies as individual carriers to which the compoundmolecules are coupled. The compounds of the present invention may alsobe coupled with soluble polymers as targetable drug carriers. Suchpolymers can include polyvinyl-pyrrolidone, pyran copolymer,polyhydroxypropylmethacrylamide-phenol,polyhydroxy-ethylaspartamidephenol, or polyethylene-oxide polylysinesubstituted with palmitoyl residues. Furthermore, the compounds of thepresent invention may be coupled to a class of biodegradable polymersuseful in achieving controlled release of a drug, for example,polylactic acid, polyepsilon caprolactone, polyhydroxy butyric acid,polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates andcross-linked or amphipathic block copolymers of hydrogels.

Formulations suitable for parenteral administration include formulationsthat comprise a sterile aqueous preparation of the active compound whichis preferably isotonic with the blood of the recipient. Suchformulations suitably comprise a solution or suspension of a compoundthat is isotonic with the blood of the recipient subject. Suchformulations may contain distilled water, 5% dextrose in distilled wateror saline and the active compound. Often it is useful to employ apharmaceutically and pharmacologically acceptable acid addition salt ofthe active compound that has appropriate solubility for the solventsemployed. Useful salts include the hydrochloride isothionate andmethanesulfonate salts. Useful formulations also comprise concentratedsolutions or solids comprising the active compound which on dilutionwith an appropriate solvent give a solution suitable for parenteraladministration.

The compounds of the present invention may be coupled to a class ofbiodegradable polymers useful in achieving controlled release of a drug,for example, polylactic acid, polyepsilon caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropyrans,polycyanoacrylates and cross-linked or amphipathic block copolymers ofhydrogels.

The pharmaceutical composition and method of the present invention mayfurther comprise other therapeutically active compounds usually appliedin the treatment of the above mentioned conditions, including:osteoporosis, osteopenia, glucocorticoid-induced osteoporosis,periodontal disease, HIV-wasting, cancer cachexia, bone fracture, bonedamage following bone reconstructive surgery, muscular dystrophies,sarcopenia, frailty, aging skin, male hypogonadism, post-menopausalsymptoms in women, female sexual dysfunction, premature ovarian failure,autoimmune disease, atherosclerosis, hypercholesterolemia,hyperlipidemia, aplastic anemia and other hematopoietic disorders,pancreatic cancer, renal cancer, arthritis and joint repair. Stillfurther, the pharmaceutical composition and method of the presentinvention may further comprise other therapeutically active compoundsusually applied in the treatment of insulin resistence, including NIDDM,obesity and growth retardation associated with obesity,hyperinsulinemia, as well as Metabolic Syndrome, or “Syndrome X” asdefined in Johannsson, J. Clin Endocrin. Metabl 82: 727-34 (1997).

For the treatment and prevention of osteoporosis, the compounds of thepresent invention may be administered in combination with abone-strengthening agent selected from: resorption inhibitors,osteoanabolic agents, and other agents beneficial for the skeletonthrough the mechanisms which are not precisely defined, such as calciumsupplements, flavenoids and vitamin D analogues. For example, thecompounds of the instant invention may be effectively administered incombination with effective amounts of other agents such as estrogens,bisphosphonates, SERMs, cathepsin K inhibitors, osteoclast integrininhibitors, vacuolar proton pump inhibitors, VEGF, thiazolidinediones,calcitonin, protein kinase inhibitors, parathyroid hormone andderivatives, calcium receptor antagonists, growth hormone secretagogues,growth hormone releasing hormone, insulin-like growth factor, bonemorphogenic protein (BMP), inhibitors of BMP antagonism, prostaglandinderivatives, fibroblast growth factors, vitamin D and derivativesthereof, Vitamin K and derivatives thereof, soy isoflavones, calcium,and fluoride salts. The conditions of periodontal disease, bonefracture, bone damage following bone reconstructive surgery may alsobenefit from these combined treatments.

In the treatment of osteoporosis, the activity of the compounds of thepresent invention are distinct from that of the resorption inhibitors:estrogens, bisphosphonates, SERMs, calcitonin and cathepsin Kinhibitors, vacuolar proton pump inhibitors, agents interfering with theRANK/RANKL/Osteoprotegerin pathway, p38 inhibitors or any otherinhibitors of osteoclast generation or osteoclast activation Rather thaninhibiting bone resorption, the compounds of structural formula Istimulate bone formation, acting preferentially on cortical bone, whichis responsible for a significant part of bone strength. The thickeningof cortical bone substantially contributes to a reduction in fracturerisk, especially fractures of the hip. The combination of the tissueselective androgen receptor modulators of structural formula I withresorption inhibitors such as estrogen, bisphosphonates, antiestrogens,SERMs, calcitonin, osteoclast integrin inhibitors HMG-CoA reductaseinhibitors, proton pump inhibitors, and cathepsin K inhibitors isparticularly useful because of the complementarity of the bone anabolicand antiresorptive actions.

Bone antiresportive agents are those agents which are known in the artto inhibit the resorption of bone and include, for example, estrogen andestrogen derivatives which include steroidal compounds having estrogenicactivity such as, for example, 17β-estradiol, estrone, conjugatedestrogen (PREMARIN®), equine estrogen, 17β-ethynyl estradiol, and thelike. The estrogen or estrogen derivative may be employed alone or incombination with a progestin or progestin derivative. Nonlimitingexamples of progestin derivatives are norethindrone andmedroxy-progesterone acetate.

Bisphosphonates are also bone anti-resorptive agents. Bisphosphonatecompounds may also be employed in combination with the compound ofstructural formula I of the present invention include:

-   4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid,-   N-methyl-4-amino-hydroxybutylidene-1,1-bisphosphonic acid,-   4-(N,N-dimethylamino-1-hydroxybutylidene-1,1-bisphosphonic acid,-   3-amino-1-hydroxypropylidene-1,1-bisphosphonic acid,-   3-(N,N-dimethylamino)-1-hydroxypropylidene-1,1-bisphosphonic acid,-   1-hydroxy-3-(N-methyl-N-pentylamino)propylidene-1,1-bisphosphonic    acid,-   1-hydroxy-2-(3-pyridyl)ethylidene-1,1-bisphosphonic acid,-   4-(hydroxymethylene-1,1-bisphosphonic acid)piperidine,-   (1-hydroxyethylidene)-bisphosphonate,-   (dichloromethylene)-bisphosphonate,-   [1-hydroxy-2-imidazopyridin-(1,2-a)-3-ylethylidene]bisphosphonate,-   (6-amino-1-hydroxyheylidene)bisphosphonate,-   [1-hydroxy-2-(1H-imidazole-1-yl)ethylidene]bisphosphonate;    and their pharmaceutically acceptable salts. Especially preferred is    alendronate, 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid    monosodium salt, trihydrate. Methods for the preparation of    bisphosphonic acids may be found in, e.g., U.S. Pat. No. 3,251,907;    U.S. Pat. No. 3,422,137; U.S. Pat. No. 3,584,125; U.S. Pat. No.    3,940,436; U.S. Pat. No. 3,944,599; U.S. Pat. No. 3,962,432; U.S.    Pat. No. 4,054,598; U.S. Pat. No. 4,267,108; U.S. Pat. No.    4,327,039; U.S. Pat. No. 4,407,761; U.S. Pat. No. 4,578,376; U.S.    Pat. No. 4,621,077; U.S. Pat. No. 4,624,947; U.S. Pat. No.    4,746,654; U.S. Pat. No. 4,761,406; U.S. Pat. No. 4,922,077. In    particular, methods for the preparation of    4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid monosodium salt    trihydrate may be found in U.S. Pat. No. 4,407,761 and U.S. Pat. No.    4,621,077.

Still further, antiestrogenic compounds such as raloxifene (see, e.g.,U.S. Pat. No. 5,393,763) clomiphene, zuclomiphene, enclomiphene,nafoxidene, CI-680, CI-628, CN-55,945-27, Mer-25, U-11, 555A, U-100A,and salts thereof, and the like (see, e.g., U.S. Pat. Nos. 4,729,999 and4,894,373) may be employed in combination with the compound ofstructural formula I in the methods and compositions of the presentinvention. These agents are also known as SERMs, or selective estrogenreceptor modulators, agents known in the art to prevent bone loss byinhibiting bone resorption via pathways believed to be similar to thoseof estrogens. These agents may beneficially be used in combination withthe compounds of the present invention to beneficially treat bonedisorders including osteoporosis. Such agents include, for example:tamoxifen, raloxifene, lasofoxifene, toremifene, azorxifene, EM-800,EM-652, TSE 424, clomiphene, droloxifene, idoxifene and levormeloxifene.(Goldstein, et al., A pharmacological review of selective oestrogenreceptor modulators. Human Reproduction Update, 6: 212-224, 2000, andLufkin, et al., The role of selective estrogen receptor modulators inthe prevention and treatment of Osteoporosis. Rheumatic Disease Clinicsof North America. 27 (1): 163-185, 2001.)

Osteoclast integrin inhibitors, also called vitronectin inhibitors andαvβ3antagonists, suppress bone resorption and may be employed incombination with the tissue selective androgen receptor modulators ofstructural formula I for the treatment of bone disorders includingosteoporosis. Peptidyl as well as peptidomimetic antagonists of the αvβ3integrin receptor have been described both in the scientific and patentliterature. For example, reference is made to W. J. Hoekstra and B. L.Poulter, Curr. Med. Chem. 5: 195-204, 1998 and references cited therein;WO 95/32710; WO 95/37655; WO 97/01540; WO 97/37655; WO 98/08840; WO98/18460; WO 98/18461; WO 98/25892; WO 98/31359; WO 98/30542; WO99/15506; WO 99/15507; WO 00/03973; EP 853084; EP 854140; EP 854145;U.S. Pat. Nos. 5,204,350; 5,217,994; 5,639,754; 5,741,796; 5,780,426;5,929,120; 5,952,341; 6,017,925; and 6,048,861. Evidence of the abilityof αvβ3 integrin receptor antagonists to prevent bone resorption invitro and in vivo has been presented (V. W. Engleman, et al., “APeptidomimetic Antagonist of the αvβ3 Integrin Inhibits Bone ResorptionIn Vitro and Prevents Osteoporosis In Vivo,” J. Clin. Invest. 99:2284-2292, 1997; S. B. Rodan, et al., “A High Affinity Non-Peptide αvβ3Ligand Inhibits Osteoclast Activity In Vitro and In Vivo,” J. BoneMiner. Res. 11: S289, 1996; J. F. Gourvest, et al., “Prevention ofOVX-Induced Bone Loss With a Non-peptidic Ligand of the αvβ3 VitronectinReceptor,” Bone 23: S612, 1998; M. W. Lark, et al., “An Orally ActiveVitronectin Receptor αvβ3 Antagonist Prevents Bone Resorption In Vitroand In Vivo in the Ovariectomized Rat,” Bone 23: S219, 1998). Other αvβ3antagonists are described in R. M. Keenan, et al., “Discovery of PotentNonpeptide Vitronectin Receptor (αvβ3) Antagonists,” J. Med. Chem. 40:2289-2292, 1997; R. M. Keenan, et al., “Benzimidazole Derivatives AsArginine Mimetics in 1,4-Benzodiazepine Nonpeptide Vitronectin Receptor(αvβ3) Antagonists,” Bioorg. Med. Chem. Lett. 8: 3165-3170, 1998; and R.M. Keenan, et al., “Discovery of an Imidazopyridine-Containing1,4-Benzodiazepine Nonpeptide Vitronectin Receptor (αvβ3) AntagonistWith Efficacy in a Restenosis Model,” Bioorg. Med. Chem. Lett. 8:3171-3176, 1998. Still other benzazepine, benzodiazepine andbenzocycloheptene αvβ3 integrin receptor antagonists are described inthe following patent publications: WO 96/00574, WO 96/00730, WO96/06087, WO 96/26190, WO 97/24119, WO 97/24122, WO 97/24124, WO98/14192, WO 98/15278, WO 99/05107, WO 99/06049, WO 99/15170, WO99/15178, WO 99/15506, and U.S. Pat. No. 6,159,964, and WO 97/34865.αvβ3 integrin receptor antagonists having dibenzocycloheptene,dibenzocycloheptane and dibenzoxazepine scaffolds have been described inWO 97/01540, WO 98/30542, WO 99/11626, WO 99/15508, WO 00/33838, U.S.Pat. Nos. 6,008,213, and 6,069,158. Other osteoclast integrin receptorantagonists incorporating backbone conformational ring constraints havebeen described in the patent literature. Published patent applicationsor issued patents disclosing antagonists having a phenyl constraintinclude WO 98/00395, WO 99/32457, WO 99/37621, WO 99/44994, WO99/45927,WO 99/52872, WO 99/52879, WO 99/52896, WO 00/06169, EP 0820,988, EP 0 820,991, U.S. Pat. Nos. 5,741,796; 5,773,644; 5,773,646;5,843,906; 5,852,210; 5,929,120; 5,952,381; 6,028,223; and 6,040,311.Published patent applications or issued patents disclosing antagonistshaving a monocyclic ring constraint include WO 99/26945, WO 99/30709, WO99/30713, WO 99/31099, WO 99/59992, WO 00/00486, WO 00/09503, EP 0796,855, EP 0 928,790, EP 0 928,793, U.S. Pat. Nos. 5,710,159;5,723,480; 5,981,546; 6,017,926; and 6,066,648. Published patentapplications or issued patents disclosing antagonists having a bicyclicring constraint include WO 98/23608, WO 98/35949, WO 99/33798, EP 0853,084, U.S. Pat. Nos. 5,760,028; 5,919,792; and 5,925,655. Referenceis also made to the following reviews for additional scientific andpatent literature that concern alpha v integrin antagonists: M. E.Duggan, et al., “Ligands to the integrin receptor αvβ3,” Exp. Opin.Ther. Patents, 10: 1367-1383, 2000; M. Gowen, et al., “Emergingtherapies for osteoporosis,” Emerging Drugs, 5: 1-43, 2000; J. S. Kerr,et al., “Small molecule αv integrin antagonists: novel anticanceragents,” Exp. Opin. Invest. Drugs, 9: 1271-1291, 2000; and W. H. Miller,et al., “Identification and in vivo efficacy of small-moleculeantagonists of integrin αvβ3 (the vitronectin receptor),” Drug DiscoveryToday, 5: 397-408, 2000.

Cathepsin K, formerly known as cathepsin O2, is a cysteine protease andis described in PCT International Application Publication No. WO96/13523, published May 9, 1996; U.S. Pat. No. 5,501,969, issued Mar. 3,1996; and U.S. Pat. No. 5,736,357, issued Apr. 7, 1998, all of which areincorporated by reference herein in their entirety. Cysteine proteases,specifically cathepsins, are linked to a number of disease conditions,such as tumor metastasis, inflammation, arthritis, and bone remodeling.At acidic pH's, cathepsins can degrade type-I collagen. Cathepsinprotease inhibitors can inhibit osteoclastic bone resorption byinhibiting the degradation of collagen fibers and are thus useful in thetreatment of bone resorption diseases, such as osteoporosis.

Members of the class of HMG-CoA reductase inhibitors, known as the“statins,” have been found to trigger the growth of new bone, replacingbone mass lost as a result of osteoporosis (The Wall Street Journal,Friday, Dec. 3, 1999, page B1). Therefore, the statins hold promise forthe treatment of bone resorption. Examples of HMG-CoA reductaseinhibitors include statins in their lactonized or dihydroxy open acidforms and pharmaceutically acceptable salts and esters thereof,including but not limited to lovastatin (see U.S. Pat. No. 4,342,767);simvastatin (see U.S. Pat. No. 4,444,784); dihydroxy open-acidsimvastatin, particularly the ammonium or calcium salts thereof;pravastatin, particularly the sodium salt thereof (see U.S. Pat. No.4,346,227); fluvastatin particularly the sodium salt thereof (see U.S.Pat. No. 5,354,772); atorvastatin, particularly the calcium salt thereof(see U.S. Pat. No. 5,273,995); cerivastatin, particularly the sodiumsalt thereof (see U.S. Pat. No. 5,177,080), rosuvastatin, also known asZD4522 (see U.S. Pat. No. 5,260,440) and pitavastatin also referred toas NK-104 or nisvastatin (see PCT international publication number WO97/23200).

Osteoclast vacuolar ATPase inhibitors, also called proton pumpinhibitors, may also be employed together with the tissue selectiveandrogen receptor modulator of structural formula I. The proton ATPasewhich is found on the apical membrane of the osteoclast has beenreported to play a significant role in the bone resorption process.Therefore, this proton pump represents an attractive target for thedesign of inhibitors of bone resorption which are potentially useful forthe treatment and prevention of osteoporosis and related metabolicdiseases (C. Farina, et al., “Selective inhibitors of the osteoclastvacuolar proton ATPase as novel bone resorption inhibitors,” DDT, 4:163-172, 1999).

The angiogenic factor VEGF has been shown to stimulate thebone-resorbing activity of isolated mature rabbit osteoclasts viabinding to its receptors on osteoclasts (M. Nakagawa, et al., “Vascularendothelial growth factor (VEGF) directly enhances osteoclastic boneresorption and survival of mature osteoclasts,” FEBS Letters, 473:161-164, 2000). Therefore, the development of antagonists of VEGFbinding to osteoclast receptors, such as KDR/Flk-1 and Flt-1, mayprovide yet a further approach to the treatment or prevention of boneresorption.

Activators of the peroxisome proliferator-activated receptor-γ (PPARγ),such as the thiazolidinediones (TZD's), inhibit osteoclast-like cellformation and bone resorption in vitro. Results reported by R. Okazaki,et al. in Endocrinology, 140, pp 5060-5065, 1999 point to a localmechanism on bone marrow cells as well as a systemic one on glucosemetabolism. Nonlimiting examples of PPARγ activators includetroglitazone, pioglitazone, rosiglitazone, and BRL 49653.

Calcitonin may also be employed together with the tissue selectiveandrogen receptor modulator of structural formula I. Calcitonin ispreferentially administered as nasal spray. Azra, et al., Calcitonin,1996, In: J. P. Bilezikian, et al. Ed. Principles of Bone Biology, SanDiego: Academic Press; and Silverman. Calcitonin,. Rheumatic DiseaseClinics of North America 27:187-196, 2001).

Protein kinase inhibitors may also be employed together with the tissueselective androgen receptor modulator of structural formula I. Kinaseinhibitors include those disclosed in WO 0117562 and are in oneembodiment selected from inhibitors of P-38. Specific embodiments ofP-38 inhibitors useful in the present invention include: SB 203580(Badger, et al., Pharmacological profile of SB 203580, a selectiveinhibitor of cytokine suppressive binding protein/p38 kinase, in animalmodels of arthritis, bone resorption, endotoxin shock and immunefunction, J. Pharmacol. Exp. Ther. 279: 1453-1461, 1996).

Osteoanabolic agents are those agents that are known in the art to buildbone by increasing the production of the bone matrix. Such osteoanabolicagents include, for example, the various forms of parathyroid hormone(PTH) such as naturally occurring PTH (1-84), PTH (1-34), analogsthereof, native or with substitutions and particularly parathyroidhormone subcutaneous injection. PTH has been found to increase theactivity of osteoblasts, the cells that form bone, thereby promoting thesynthesis of new bone (Modern Drug Discovery, Vol. 3, No. 8, 2000). Instudies reported at the First World Congress on Osteoporosis held inChicago in June 2000, women in combined PTH-estrogen therapy exhibited a12.8% increase in spinal bone mass and a 4.4% increase in total hipmass. Another study presented at the same meeting showed that PTH couldincrease bone size as well as density. A clinical trial of the effect ofthe human parathyroid hormone 1-34 fragment [hPTH(1-34)] onpostmenopausal osteoporotic women resulted in ≧65% reduction in spinefractures and a 54% reduction in nonvertebral fractures, after a medianof 22 months of treatment (J. M. Hock, Bone, 27: 467-469, 2000 and S.Mohan, et al., Bone, 27: 471-478, 2000, and references cited therein).Thus, PTH and fragments thereof, such as hPTH(1-34), may prove to beefficacious in the treatment of osteoporosis alone or in combinationwith other agents, such as the tissue selective androgen receptormodulators of the present invention.

Also useful in combination with the SARMs of the present invention arecalcium receptor antagonists which induce the secretion of PTH asdescribed by Gowen, et al., in Antagonizing the parathyroid calciumreceptor stimulates parathyroid hormone secretion and bone formation inosteopenic rats, J Clin Invest. 105 :1595-604, 2000.

Growth hormone secretagogues, growth hormone, growth hormone releasinghormone and insulin-like growth factor and the like are alsoosteoanabolic agents which may be employed with the compounds accordingto structural formula I for the treatment of osteoporosis.Representative growth hormone secretagogues are disclosed in U.S. Pat.No. 3,239,345; U.S. Pat. No. 4,036,979; U.S. Pat. No. 4,411,890; U.S.Pat. No. 5,206,235; U.S. Pat. No. 5,283,241; U.S. Pat. No. 5,284,841;U.S. Pat. No. 5,310,737; U.S. Pat. No. 5,317,017; U.S. Pat. No.5,374,721; U.S. Pat. No. 5,430,144; U.S. Pat. No. 5,434,261; U.S. Pat.No. 5,438,136; U.S. Pat. No. 5,494,919; U.S. Pat. No. 5,494,920; U.S.Pat. No. 5,492,916; U.S. Pat. No. 5,536,716; EPO Patent Pub. No.0,144,230; EPO Patent Pub. No. 0,513,974; PCT Patent Pub. No. WO94/07486; PCT Patent Pub. No. WO 94/08583; PCT Patent Pub. No. WO94/11012; PCT Patent Pub. No. WO 94/13696; PCT Patent Pub. No. WO94/19367; PCT Patent Pub. No. WO 95/03289; PCT Patent Pub. No. WO95/03290; PCT Patent Pub. No. WO 95/09633; PCT Patent Pub. No. WO95/11029; PCT Patent Pub. No. WO 95/12598; PCT Patent Pub. No. WO95/13069; PCT Patent Pub. No. WO 95/14666; PCT Patent Pub. No. WO95/16675; PCT Patent Pub. No. WO 95/16692; PCT Patent Pub. No. WO95/17422; PCT Patent Pub. No. WO 95/17423; PCT Patent Pub. No. WO95/34311; PCT Patent Pub. No. WO 96/02530; Science 260, 1640-1643, Jun.11, 1993; Ann. Rep. Med. Chem., 28, 177-186 (1993); Bioorg. Med. Chem.Ltrs., 4(22), 2709-2714, 1994; and Proc. Natl. Acad. Sci. USA 92,7001-7005, July 1995.

Insulin-like growth factor (IGF) may also be employed together with thetissue selective androgen receptor modulator of structural formula I.Insulin-like growth factors may be selected from Insulin-like GrowthFactor I, alone or in combination with IGF binding protein 3 and IGF II.(Johannson and Rosen, The IGFs as potential therapy for metabolic bonediseases, 1996, In: Bilezikian, et. al. Ed. Principles of Bone Biology.San Diego: Academic Press; and Ghiron, et al., Effects of recombinantinsulin-like growth factor-I and growth hormone on bone turnover inelderly women, J Bone Miner Res. 10:1844-52, 1995).

Bone morphogenic protein (BMP) may also be employed together with thetissue selective androgen receptor modulator of structural formula I.Bone morphogenic protein includes BMP 2, 3, 5, 6, 7, as well as relatedmolecules TGF beta and GDF 5. Rosen, et al., Bone morphogeneticproteins. 1996. In: J. P. Bilezikian, et. al. Ed. Principles of BoneBiology, San Diego: Academic Press; and Wang E A, Bone morphogeneticproteins (BMPs): therapeutic potential in healing bony defects. TrendsBiotechnol. 11:379-83, 1993.

Inhibitors of BMP antagonism may also be employed together with thetissue selective androgen receptor modulator of structural formula I.BMP antagonist inhibitors are in one embodiment selected from inhibitorsof the BMP antagonists SOST, noggin, chordin, gremlin, and dan (Massagueand Chen Controlling TGF-beta signaling, Genes Dev. 14:627-44, 2000;Aspenberg, et al., The bone morphogenetic proteins antagonist Noggininhibits membranous ossification, J Bone Miner Res. 16:497-500, 2001;Brunkow, et al., Bone dysplasia sclerostenosis results from loss of theSOST gene product, a novel cystine knot-containing protein, Am J HumGenet. 68: 577-89, 2001).

Prostaglandin derivatives may also be employed together with the tissueselective androgen receptor modulator of structural formula I.Prostaglandin derivatives are in one embodiment selected from agonistsof prostaglandin receptor EP1, EP2, EP4, FP and IP or a derivativethereof. Pilbeam, et al., Prostaglandins and bone metabolism, 1996, In:Bilezikian, et al. Ed. Principles of Bone Biology. San Diego: AcademicPress; Weinreb, et al., Expression of the prostaglandin E(2) (PGE(2))receptor subtype EP(4) and its regulation by PGE(2) in osteoblastic celllines and adult rat bone tissue(1), Bone. 28(3):275-81, 2001.

Fibroblast growth factors may also be employed together with the tissueselective androgen receptor modulator of structural formula I.Fibroblast growth factors include aFGF, bFGF and related peptides withFGF activity. Hurley Florkiewicz; Fibroblast growth factor and vascularendothelial growth factor families. 1996. In: J. P. Bilezikian, et. al.Ed. Principles of Bone Biology. San Diego: Academic Press.

In addition to bone resorption inhibitors and osteoanabolic agents,there are also other agents known to be beneficial for the skeletonthrough the mechanisms which are not precisely defined. These agents mayalso be favorably combined with the tissue selective androgen receptormodulator of structural formula I.

Vitamin D and Vitamin D derivatives may also be employed together withthe tissue selective androgen receptor modulator of structural formulaI. Vitamin D and Vitamin D derivatives include: natural vitamin D,25-OH-vitamin D3, 1α,25(OH)2 vitamin D3, 1α-OH-vitamin D3, 1α-OH-vitaminD2, dihydrotachysterol, 26,27-F6-1α,25(OH)2 vitamin D3,19-nor-1α,25(OH)2 vitamin D3, 22-oxacalcitriol, calcipotriol,1α,25(OH)2-16-ene-23-yne-vitamin D3 (Ro 23-7553), EB1089,20-epi-1α,25(OH)2 vitamin D3, KH1060, ED71, 1α,24(S)—(OH)2 vitamin D3,1α,24(R)—(OH)2 vitamin D3. Jones G. Pharmacological mechanisms oftherapeutics: vitamin D and analogs. 1996. In: J. P. Bilezikian, et. al.Ed. Principles of Bone Biology. San Diego: Academic Press.

Vitamin K and Vitamin K derivatives may also be employed together withthe tissue selective androgen receptor modulator of structural formulaI. Vitamin K and Vitamin K derivatives include: menatetrenone (vitaminK2). Shiraki, et al., Vitamin K2 (menatetrenone) effectively preventsfractures and sustains lumbar bone mineral density in osteoporosis, JBone Miner Res. 15: 515-21.

Soy isoflavones including ipriflavone may be employed together with thetissue selective androgen receptor modulator of structural formula I.

Fluoride salts, including sodium fluoride (NaF) or monosodiumfluorophosphate (WFP) may also be employed together with the tissueselective androgen receptor modulator of structural formula I. Dietarycalcium supplements may also be employed together with the tissueselective androgen receptor modulator of structural formula I. Dietarycalcium supplements include calcium carbonate, calcium citrate andnatural calcium salts. Heaney, Calcium, 1996, In: J. P. Bilezikian, et.al. Ed. Principles of Bone Biology. San Diego: Academic Press.

Daily dosage ranges for bone resorption inhibitors, osteoanabolic agentsand other agents which may be used to benefit the skeleton when used incombination with the compounds of structural formula I are those whichare known in the art. In such combinations, generally the daily dosagerange for the tissue selective androgen receptor modulator of structuralformula I is 0.01 to 1000 mg per adult human per day, more preferablyfrom 0.1 to 200 mg/day. However, adjustments to decrease the dose ofeach agent may be made due to the increased efficacy of the combinedagent.

In particular, when a bisphosphonate is employed, dosages of 2.5 to 100mg/day (measured as the free bisphosphonic acid) are appropriate fortreatment, more preferably 5 to 20 mg/day, especially about 10 mg/day.Prophylactically, doses of about 2.5 to about 10 mg/day and especiallyabout 5 mg/day should be employed. For reduction in side-effects, it maybe desirable to administer the combination of the compound of structuralformula I and the bisphosphonate once a week. For once weeklyadministration, doses of about 15 mg to 700 mg per week ofbisphosphonate and 0.07 to 7000 mg of the compound of structural formulaI may be employed, either separately, or in a combined dosage form. Thecompound of structural formula I may be favorably administered in acontrolled-release delivery device, particularly for once weeklyadministration.

For the treatment of atherosclerosis, hypercholesterolemia,hyperlipidemia, the compounds of structural formula I may be effectivelyadministered in combination with one or more additional active agents.The additional active agent or agents can be lipid altering compoundssuch as HMG-CoA reductase inhibitors, or agents having otherpharmaceutical activities, or agents that have both lipid-alteringeffects and other pharmaceutical activities. Examples of HMG-CoAreductase inhibitors include statins in their lactonized or dihydroxyopen acid forms and pharmaceutically acceptable salts and estersthereof, including but not limited to lovastatin (see U.S. Pat. No.4,342,767); simvastatin (see U.S. Pat. No. 4,444,784); dihydroxyopen-acid simvastatin, particularly the ammonium or calcium saltsthereof; pravastatin, particularly the sodium salt thereof (see U.S.Pat. No. 4,346,227); fluvastatin particularly the sodium salt thereof(see U.S. Pat. No. 5,354,772); atorvastatin, particularly the calciumsalt thereof (see U.S. Pat. No. 5,273,995); cerivastatin, particularlythe sodium salt thereof (see U.S. Pat. No. 5,177,080), and nisvastatinalso referred to as NK-104 (see PCT international publication number WO97/23200). Additional active agents which may be employed in combinationwith a compound of structural formula I include, but are not limited to,HMG-CoA synthase inhibitors; squalene epoxidase inhibitors; squalenesynthetase inhibitors (also known as squalene synthase inhibitors),acyl-coenzyme A: cholesterol acyltransferase (ACAT) inhibitors includingselective inhibitors of ACAT-1 or ACAT-2 as well as dual inhibitors ofACAT1 and -2; microsomal triglyceride transfer protein (MTP) inhibitors;probucol; niacin; cholesterol absorption inhibitors such as SCH-58235also known as ezetimibe and1-(4-fluorophenyl)-3(R)-[3(S)-(4-fluorophenyl)-3-hydroxypropyl)]-4(S)-(4-hydroxyphenyl)-2-azetidinone,which is described in U.S. Pat. Nos. 5,767,115 and 5,846,966; bile acidsequestrants; LDL (low density lipoprotein) receptor inducers; plateletaggregation inhibitors, for example glycoprotein IIb/IIIa fibrinogenreceptor antagonists and aspirin; human peroxisome proliferatoractivated receptor gamma (PPARγ) agonists including the compoundscommonly referred to as glitazones for example troglitazone,pioglitazone and rosiglitazone and, including those compounds includedwithin the structural class known as thiazolidinediones as well as thosePPARγ agonists outside the thiazolidinedione structural class; PPARαagonists such as clofibrate, fenofibrate including micronizedfenofibrate, and gemfibrozil; PPAR dual α/γ agonists; vitamin B₆ (alsoknown as pyridoxine) and the pharmaceutically acceptable salts thereofsuch as the HCl salt; vitamin B₁₂ (also known as cyanocobalamin); folicacid or a pharmaceutically acceptable salt or ester thereof such as thesodium salt and the methylglucamine salt; anti-oxidant vitamins such asvitamin C and E and beta carotene; beta-blockers; angiotensin IIantagonists such as losartan; angiotensin converting enzyme inhibitorssuch as enalapril and captopril; calcium channel blockers such asnifedipine and diltiazam; endothelian antagonists; agents such as LXRligands that enhance ABC1 gene expression; bisphosphonate compounds suchas alendronate sodium; and cyclooxygenase-2 inhibitors such as rofecoxiband celecoxib as well as other agents known to be useful in thetreatment of these conditions.

Daily dosage ranges for HMG-CoA reductase inhibitors when used incombination with the compounds of structural formula I correspond tothose which are known in the art. Similarly, daily dosage ranges for theHMG-CoA synthase inhibitors; squalene epoxidase inhibitors; squalenesynthetase inhibitors (also known as squalene synthase inhibitors),acyl-coenzyme A: cholesterol acyltransferase (ACAT) inhibitors includingselective inhibitors of ACAT-1 or ACAT-2 as well as dual inhibitors ofACAT1 and -2; microsomal triglyceride transfer protein (MTP) inhibitors;probucol; niacin; cholesterol absorption inhibitors including ezetimibe;bile acid sequestrants; LDL (low density lipoprotein) receptor inducers;platelet aggregation inhibitors, including glycoprotein IIb/IIIafibrinogen receptor antagonists and aspirin; human peroxisomeproliferator activated receptor gamma (PPARγ) agonists; PPARα agonists;PPAR dual α/γ agonists; vitamin B₆; vitamin B₁₂; folic acid;anti-oxidant vitamins; beta-blockers; angiotensin II antagonists;angiotensin converting enzyme inhibitors; calcium channel blockers;endothelian antagonists; agents such as LXR ligands that enhance ABC1gene expression; bisphosphonate compounds; and cyclooxygenase-2inhibitors also correspond to those which are known in the art, althoughdue to the combined action with the compounds of structural formula I,the dosage may be somewhat lower when administered in combination.

In accordance with the method of the present invention, the individualcomponents of the combination can be administered separately atdifferent times during the course of therapy or concurrently in dividedor single combination forms. The instant invention is therefore to beunderstood as embracing all such regimes of simultaneous or alternatingtreatment and the term “administering” is to be interpreted accordingly.It will be understood that the scope of combinations of the compounds ofthis invention with other agents useful for treating diseases caused byandrogen deficiency or that can be ameliorated by addition of androgen.

The following examples are provided to further illustrate details forthe preparation and use of the compounds of the present invention. Theexamples are not intended to be limitations on the scope of the instantinvention in any way, and they should not be so construed. Furthermore,the compounds described in the following examples are not to beconstrued as forming the only genus that is considered as the invention,and any combination of the compounds or their moieties may itself form agenus. Those skilled in the art will readily understand that knownvariations of the conditions and processes of the following preparativeprocedures can be used to prepare these compounds. All temperatures arein degrees Celsius unless noted otherwise.

Abbreviations: Ac represents acetyl; AR is the androgen receptor; cPr iscyclopropyl; ddWater is distilled, deionized water; DMEM is Dulbecco'sModified Eagle Media; DMF is dimethyl formamide; EDTA isethylenediaminetetraacetic acid; EGTA is ethylenebis(oxyethylenenitrolo)tetraacetic acid; Et represents ethyl; FCS isfetal calf serum; HAP is hydroxylapatite; hAR is the human androgenreceptor; iPr is isopropyl; Me is methyl; MEM is Minimum EssentialMedia; min. is minute; NMM is N-methyl morpholine; PBS is phosphatebuffered saline (8 g NaCl, 0.2 g KCl, 1.44 g Na₂HPO₄, 0.24 KH₂PO₄dissolve into H₂O to make 1 L and adjust pH to 7.4 with HCl); Ph isphenyl; pQCT is peripheral quantitative computer tomography; R1881 ismethyltrienolone, an androgen receptor agonist; RhAR is the rhesusandrogen receptor; SARM is a tissue selective androgen receptormodulator; SEAP is secreted alkaline phosphatase; TAC is triamcinoloneacetonide; THF is tetrahydrofuran.

EXAMPLE 1 Preparation of4-methyl-17β-(2-trifluoromethylbenzamido)-4-aza-5α-androst-1-ene-3one(1-3)

4-methyl-17β-amino-4-aza-5α-androst-1-ene-3-one (1-2).

Acid 1-1 (7.6 g, 22.9 mmol; prepared as described in WO 93/23420), CHCl₃(72 mL) and H₂SO₄ (36 mL) was heated to 52° C. Sodium azide (3.1 g, 48.4mmol) was added in three portions over 15 minutes. After the lastaddition, the mixture was heated to 60° C. for 30 minutes. The mixturewas then allowed to cool to ambient temperature and poured into 200 g ofice. To this mixture was then added 200 mL of CHCl₃ and then 50% w/wNaOH until the aqueous pH=12. The organic portion was separated. Theaqueous portion was extracted with CHCl₃ (2×200 mL). The combinedorganic portions were washed with 1/4 5 M NaOH/brine (70 mL), dried(MgSO₄) and then concentrated to provide the amine 1-2 as a white solid.

HRMS (FAB, M+1) found 303.2437.

4-methyl-17β-(2-trifluoromethylbenzamido)-4-aza-5α-androst-1-ene-3-one(1-3).

Amine 1-2 (250 mg, 0.828 mmol), NEt₃ (250 μL, 1.6 mmol),2-trifluoromethylbenzoyl chloride (173 mg) and CH₂Cl₂ (1 mL) werecombined and then stirred overnight. The reaction was diluted with 1 mLCH₂Cl₂ and then washed with saturated aqueous K₂CO₃. The organic portionwas separated and purified by flash chromatography (silica,hexanes→EtOAc) provided compound 1-3 as a white solid.

HRMS (FAB, M+1) found 475.2597

Utilizing the same general procedure as described for compound 1-3 inExample 1, and by varying the acid chloride reagent, compounds 1-4through 1-86 were prepared (Table 1); mass spectral characterization ofthese compounds is listed in Table 2.

TABLE 1

1-2

1-3

1-4

1-5

1-6

1-7

1-8

1-9

1-10

1-11

1-12

1-13

1-14

1-15

1-16

1-17

1-18

1-19

1-20

1-21

1-22

1-23

1-24

1-25

1-26

1-27

1-28

1-29

1-30

1-31

1-32

1-33

1-34

1-35

1-36

1-37

1-38

1-39

1-40

1-41

1-42

1-43

1-44

1-45

1-46

1-47

1-48

1-49

1-50

1-51

1-52

1-53

1-54

1-55

1-56

1-57

1-58

1-59

1-60

1-61

1-62

1-63

1-64

1-65

1-66

1-67

1-68

1-69

1-70

1-71

1-72

1-73

1-74

1-75

1-76

1-77

1-78

1-79

1-80

1-81

1-82

1-83

1-84

1-85

1-86

TABLE 2 Compound Number Name [M + H]+ Found 1-2 4-methyl-17β-amino-4-aza-5α-androst-1-ene-3-one 303.2437 1-3 4-methyl-17β-(2-trifluoromethylbenzamido)-4-aza-5α- 475.2597androst-1-ene-3-one 1-4 4-methyl-17β-(3-trifluoromethylbenzamido)-4-aza-5α- 475.2587androst-1-ene-3-one 1-5 4-methyl-17β-(2-methoxybenzamido)-4-aza-5α-androst- 437.2813 1-ene-3-one1-6  4-methyl-17β-(3-methoxybenzamido)-4-aza-5α-androst- 437.28071-ene-3-one 1-7  4-methyl-17β-(4-methoxybenzamido)-4-aza-5α-androst-437.2794 1-ene-3-one 1-8 4-methyl-17β-(4-cyanobenzamido)-4-aza-5α-androst-1- 432.2630 ene-3-one1-9  4-methyl-17β-(2-chloro-pyrid-3-yl-amido)-4-aza-5α- 442.2246androst-1-ene-3-one 1-104-methyl-17β-(pyrid-2-yl-amido)-4-aza-5α-androst-1-ene- 408.2655 3-one1-11 4-methyl-17β-(pyrid-4-yl-amido)-4-aza-5α-androst-1-ene- 408.26553-one 1-12 4-methyl-17β-(4-(carboxymethyl)benzamido)-4-aza-5α- 465.2734androst-1-ene-3-one 1-134-methyl-17β-(pyrid-3-yl-amido)-4-aza-5α-androst-1-ene- 408.2650 3-one1-14 4-methyl-17β-(2-fluorobenzamido)-4-aza-5α-androst-1- 425.2617ene-3-one 1-15 4-methyl-17β-(3-fluorobenzamido)-4-aza-5α-androst-1-425.2598 ene-3-one 1-164-methyl-17β-(4-fluorobenzamido)-4-aza-5α-androst-1- 425.2603 ene-3-one1-17 4-methyl-17β-(2,4-difluorobenzamido)-4-aza-5α-androst- 443.25111-ene-3-one 1-18 4-methyl-17β-(4-chlorobutyramido)-4-aza-5α-androst-1-407.2485 ene-3-one 1-194-methyl-17β-(4-bromobutyramido)-4-aza-5α-androst-1- 465.2126 ene-3-one1-20 Carbamic acid, [(5α,17β)-3-oxo-4-methyl-azaandrost-1- 453.1757ene-17-yl]-2-bromoethyl ester 1-214-methyl-17β-(2-methylpropamido)-4-aza-5α- 373.2871 androst-1-ene-3-one1-22 4-methyl-17β-(2-methoxyacetamido)-4-aza-5α- 375.2661androst-1-ene-3-one 1-234-methyl-17β-(cyclopropamido)-4-aza-5α-androst-1- 371.2707 ene-3-one1-24 4-methyl-17β-(acetamido)-4-aza-5α-androst-1-ene- 345.2558 3-one1-25 4-methyl-17β-(trifluoroacetamido)-4-aza-5α-androst- 399.22571-ene-3-one 1-26 4-methyl-17β-(3,3,3-trifluoropropionamido)-4-aza-413.2411 5α-androst-1-ene-3-one 1-274-methyl-17β-(2-cyanoacetamido)-4-aza-5α- 370.2490 androst-1-ene-3-one1-28 4-methyl-17β-(2-methyl-2-hydroxypropamido)-4-aza- 389.27925α-androst-1-ene-3-one 1-294-methyl-17β-(thiazo-4-yl-amido)-4-aza-5α-androst- 414.2185 1-ene-3-one1-30 4-methyl-17β-(pyrimid-2-yl-amido)-4-aza-5α- 409.2591androst-1-ene-3-one 1-31 4-methyl-17β-(pyrimid-4-yl-amido)-4-aza-5α-409.2578 androst-1-ene-3-one 1-324-methyl-17β-(oxazo-5-yl-amido)-4-aza-5α-androst- 398.2410 1-ene-3-one1-33 4-methyl-17β-(1-methyl-imidazo-2-yl-amido)-4-aza- 411.27435α-androst-1-ene-3-one 1-344-methyl-17β-(furan-3-yl-amido)-4-aza-5α-androst- 397.2461 1-ene-3-one1-35 4-methyl-17β-(furan-2-yl-amido)-4-aza-5α-androst- 397.24721-ene-3-one 1-36 4-methyl-17β-(thiophene-2-yl-amido)-4-aza-5α- 413.2231androst-1-ene-3-one 1-37 4-methyl-17β-(thiophene-3-yl-amido)-4-aza-5α-413.2229 androst-1-ene-3-one 1-384-methyl-17β-(pyridazin-2-yl-amido)-4-aza-5α- 409.2581androst-1-ene-3-one 1-394-methyl-17β-(5-methyl-pyridin-2-yl-amido)-4-aza- 422.27875α-androst-1-ene-3-one 1-404-methyl-17β-(5-chloro-pyridin-2-yl-amido)-4-aza- 442.22285α-androst-1-ene-3-one 1-414-methyl-17β-(quinoline-2-yl-amido)-4-aza-5α- 458.2786androst-1-ene-3-one 1-42 4-methyl-17β-(quinoline-8-yl-amido)-4-aza-5α-458.2788 androst-1-ene-3-one 1-434-methyl-17β-(isoquinoline-8-yl-amido)-4-aza-5α- 458.2793androst-1-ene-3-one 1-44 4-methyl-17β-(2-chlorobenzamido)-4-aza-5α-441.2299 androst-1-ene-3-one 1-454-methyl-17β-(3-chlorobenzamido)-4-aza-5α- 441.2292 androst-1-ene-3-one1-46 4-methyl-17β-(4-chlorobenzamido)-4-aza-5α- 441.2292androst-1-ene-3-one 1-474-methyl-17β-(formamido)-4-aza-5α-androst-1-ene- 331.2375 3-one 1-484-methyl-17β-[(2-trifluoromethylphenyl)acetamido]-4- 489.2724aza-5α-androst-1-ene-3-one 1-494-methyl-17β-[(4-trifluoromethylphenyl)acetamido]-4- 489.2724aza-5α-androst-1-ene-3-one 1-504-methyl-17β-[(2-chlorophenyl)acetamido]-4-aza-5α- 455.2460androst-1-ene-3-one 1-514-methyl-17β-[(3-chlorophenyl)acetamido]-4-aza-5α- 455.2460androst-1-ene-3-one 1-524-methyl-17β-[(4-chlorophenyl)acetamido]-4-aza-5α- 455.2460androst-1-ene-3-one 1-534-methyl-17β-[(2,4-dichlorophenyl)acetamido]-4-aza- 489.20705α-androst-1-ene-3-one 1-544-methyl-17β-[(3-fluorophenyl)acetamido]-4-aza-5α- 439.2756androst-1-ene-3-one 1-554-methyl-17β-[(4-fluorophenyl)acetamido]-4-aza-5α- 439.2756androst-1-ene-3-one 1-564-methyl-17β-[(2-methoxyphenyl)acetamido]-4-aza- 451.29555α-androst-1-ene-3-one 1-574-methyl-17β-[(3-methoxyphenyl)acetamido]-4-aza- 451.29555α-androst-1-ene-3-one 1-584-methyl-17β-[(2,5-dimethoxyphenyl)acetamido]-4- 481.3061aza-5α-androst-1-ene-3-one 1-594-methyl-17β-[(3,5-difluorophenyl)acetamido]-4-aza- 457.26615α-androst-1-ene-3-one 1-604-methyl-17β-[(3-nitrophenyl)acetamido]-4-aza-5α- 466.2701androst-1-ene-3-one 1-614-methyl-17β-(tetrahydrofuran-2-yl-amido)-4-aza- 401.27995α-androst-1-ene-3-one 1-624-methyl-17β-(tetrahydrofuran-3-yl-amido)-4-aza- 401.27995α-androst-1-ene-3-one 1-634-methyl-17β-(4-ethyl-pyridin-2-yl-amido)-4-aza-5α- 436.2959androst-1-ene-3-one 1-644-methyl-17β-(3-methyl-pyridin-2-yl-amido)-4-aza- 422.28025α-androst-1-ene-3-one 1-654-methyl-17β-(3-bromo-pyridin-2-yl-amido)-4-aza- 486.17515α-androst-1-ene-3-one 1-664-methyl-17β-(4-bromo-pyridin-2-yl-amido)-4-aza- 486.17515α-androst-1-ene-3-one 1-674-methyl-17β-[(2-phenylcyclopropyl)amido]-4-aza- 447.30065α-androst-1-ene-3-one 1-684-methyl-17β-[(2-fluorophenyl)acetamido]-4-aza- 439.27565α-androst-1-ene-3-one 1-694-methyl-17β-[(pyrid-2-yl)acetamido]-4-aza-5α- 422.2802androst-1-ene-3-one 1-70 4-methyl-17β-[(pyrid-3-yl)acetamido]-4-aza-5α-422.2802 androst-1-ene-3-one 1-714-methyl-17β-[(4-methoxyphenyl)acetamido]-4-aza- 451.29555α-androst-1-ene-3-one 1-724-methyl-17β-[3-(2-fluorophenyl)propionamido]-4- 453.2924aza-5α-androst-1-ene-3-one 1-734-methyl-17β-[3-(4-fluorophenyl)propionamido]-4- 453.2931aza-5α-androst-1-ene-3-one 1-74 4-methyl-17β-[3-(4- 503.2874trifluoromethylphenyl)propionamido]-4-aza-5α- androst-1-ene-3-one 1-754-methyl-17β-[3-(2-chlorophenyl)propionamido]-4- 469.2635aza-5α-androst-1-ene-3-one 1-764-methyl-17β-[3-(3-chlorophenyl)propionamido]-4- 469.2633aza-5α-androst-1-ene-3-one 1-774-methyl-17β-[3-(4-chlorophenyl)propionamido]-4- 469.2638aza-5α-androst-1-ene-3-one 1-784-methyl-17β-[2-trifluoromethylcinnamido]-4-aza-5α- 501.2723androst-1-ene-3-one 1-794-methyl-17β-[2-chlorocinnamido]-4-aza-5α-androst- 467.2478 1-ene-3-one1-80 4-methyl-17β-[2-fluorocinnamido]-4-aza-5α-androst-1- 451.2752ene-3-one 1-81 4-methyl-17β-[4-(2,5-dichlorophenyl)butanamido]-4-517.2381 aza-5α-androst-1-ene-3-one 1-824-methyl-17β-[4-(2-nitrophenyl)butanamido]-4-aza-5α- 494.3009androst-1-ene-3-one 1-834-methyl-17β-[4-(3,4-dimethoxyphenyl)butanamido]-4- 509.336aza-5α-androst-1-ene-3-one 1-844-methyl-17β-[propionamido]-4-aza-5α-androst-1-ene 359.2707 3-one 1-854-methyl-17β-[butyramido]-4-aza-5α-androst-1-ene-3- 373.2844 one 1-864-methyl-17β-[(2-methyl)cyclopropamido]-4-aza-5α- 385.2842androst-1-ene-3-one

EXAMPLE 2 Preparation of4-methyl-17β-(2-trifluoromethylbenzamido)-4-aza-5α-androst-1-ene-3-one(2-2)

Amine 1-2 (100 mg, 0.331 mmol), diisopropylethylamine (120 μL, 0.662mmol), phenyl chloroformate (50 μL, 0.397 mmol) and CH₂Cl₂ (1 mL) werecombined and then stirred overnight. The organic portion was separated,dried over magnesium sulfate, and evaporated. The resulting residue wasand purified by flash chromatography (silica, hexanes→EtOAc) providingcompound 2-2 as a white solid.

HRMS (FAB, M+1) found 423.2672

Utilizing the same general procedure as described for compound 2-2 inExample 2, and by varying the chloroformate reagent, compounds 2-3through 2-40 were prepared (Table 3); mass spectral characterization ofthese compounds is listed in Table 4.

TABLE 3

2-2

2-3

2-4

2-5

2-6

2-7

2-8

2-9

2-10

2-11

2-12

2-13

2-14

2-15

2-16

2-17

2-18

2-19

2-20

2-21

2-22

2-23

2-24

2-25

2-26

2-27

2-28

2-29

2-30

2-31

2-32

2-33

2-34

2-35

2-36

2-37

2-38

2-39

2-40

TABLE 4 Com- Found pound [M + Number Name H]+ 2-2  Carbamic acid,[(5α,17β)-3-oxo-4-methyl- 423.2672 azaandrost-1-ene-17-yl]-phenyl ester2-3  Carbamic acid, [(5α,17β)-3-oxo-4-methyl- 453.1757azaandrost-1-ene-17-yl]-2-bromoethyl ester 2-4  Carbamic acid,[(5α,17β)-3-oxo-4-methyl- 457.2283azaandrost-1-ene-17-yl]-4-chlorophenyl ester 2-5  Carbamic acid,[(5α,17β)-3-oxo-4-methyl- 468.2535 azaandrost-1-ene-17-yl]-4-nitrophenylester 2-6  Carbamic acid, [(5α,17β)-3-oxo-4-methyl- 437.2810azaandrost-1-ene-17-yl]-4-methylphenyl ester 2-7  Carbamic acid,[(5α,17β)-3-oxo-4-methyl- 501.1792 azaandrost-1-ene-17-yl]-4-bromophenylester 2-8  Carbamic acid, [(5α,17β)-3-oxo-4-methyl- 441.2574azaandrost-1-ene-17-yl]-4-fluorophenyl ester 2-9  Carbamic acid,[(5α,17β)-3-oxo-4-methyl- 453.2775azaandrost-1-ene-17-yl]-4-methoxophenyl ester 2-10 Carbamic acid,[(5α,17β)-3-oxo-4-methyl- 468.2531 azaandrost-1-ene-17-yl]-2-nitrophenylester 2-11 Carbamic acid, [(5α,17β)-3-oxo-4-methyl- 473.2840azaandrost-1-ene-17-yl]-3-naphthyl ester 2-12 Carbamic acid,[(5α,17β)-3-oxo-4-methyl- 491.2551azaandrost-1-ene-17-yl]-3-trifluoromethylphenyl ester 2-13 Carbamicacid, [(5α,17β)-3-oxo-4-methyl- 375.2661 azaandrost-1-ene-17-yl]-ethylester 2-14 Carbamic acid, [(5α,17β)-3-oxo-4-methyl- 437.2818azaandrost-1-ene-17-yl]-benzyl ester 2-15 Carbamic acid,[(5α,17β)-3-oxo-4-methyl- 429.3256azaandrost-1-ene-17-yl]-2,2,2-trifluoroethyl ester and 429.2411 2-16Carbamic acid, [(5α,17β)-3-oxo-4-methyl- 417.3107azaandrost-1-ene-17-yl]-2-methoxyethyl ester 2-17 Carbamic acid,[(5α,17β)-3-oxo-4-methyl- 393.2553azaandrost-1-ene-17-yl]-(2,2-dimethylpropy) ester 2-18 Carbamic acid,[(5α,17β)-3-oxo-4-methyl- 387.2666 azaandrost-1-ene-17-yl]-2-fluoroethylester 2-18 Carbamic acid, [(5α,17β)-3-oxo-4-methyl- 361.2514azaandrost-1-ene-17-yl]-allyl ester 2-20 Carbamic acid,[(5α,17β)-3-oxo-4-methyl- 385.2514 azaandrost-1-ene-17-yl]-methyl ester2-21 Carbamic acid, [(5α,17β)-3-oxo-4-methyl- 403.2986azaandrost-1-ene-17-yl]-1-propynoic ester 2-22 Carbamic acid,[(5α,17β)-3-oxo-4-methyl- 442.2344azaandrost-1-ene-17-yl]-(2-methyl-2-butyl) ester 2-23 Carbamic acid,[(5α,17β)-3-oxo-4-methyl- 491.2510azaandrost-1-ene-17-yl]-2-(trifluoromethyl)phenyl ester 2-24 Carbamicacid, [(5α,17β)-3-oxo-4-methyl- 491.2523azaandrost-1-ene-17-yl]-4-(trifluoromethyl)phenyl ester 2-25 Carbamicacid, [(5α,17β)-3-oxo-4-methyl- 441.2583azaandrost-1-ene-17-yl]-2-fluorophenyl ester 2-26 Carbamic acid,[(5α,17β)-3-oxo-4-methyl- 441.2595azaandrost-1-ene-17-yl]-3-fluorophenyl ester 2-27 Carbamic acid,[(5α,17β)-3-oxo-4-methyl- 391.2629azaandrost-1-ene-17-yl]-(2-hydroxy-1-ethyl) ester 2-28 Carbamic acid,[(5α,17β)-3-oxo-4-methyl- 453.2745azaandrost-1-ene-17-yl]-2-methoxyphenyl ester 2-29 Carbamic acid,[(5α,17β)-3-oxo-4-methyl- 453.2775azaandrost-1-ene-17-yl]-3-methoxyphenyl ester 2-30 Carbamic acid,[(5α,17β)-3-oxo-4-methyl- 467.291 azaandrost-1-ene-17-yl]-2-ethoxyphenylester 2-31 Carbamic acid, [(5α,17β)-3-oxo-4-methyl- 467.2862azaandrost-1-ene-17-yl]-3-ethoxyphenyl ester 2-32 Carbamic acid,[(5α,17β)-3-oxo-4-methyl- 467.2865azaandrost-1-ene-17-yl]-4-ethoxyphenyl ester 2-33 Carbamic acid,[(5α,17β)-3-oxo-4-methyl- 457.2229azaandrost-1-ene-17-yl]-4-chlorophenyl ester 2-34 Carbamic acid,[(5α,17β)-3-oxo-4-methyl- 457.2216azaandrost-1-ene-17-yl]-3-chlorophenyl ester 2-35 Carbamic acid,[(5α,17β)-3-oxo-4-methyl- 507.2434azaandrost-1-ene-17-yl]-3-(trifluoromethoxy)phenyl ester 2-36 Carbamicacid, [(5α,17β)-3-oxo-4-methyl- 507.2487azaandrost-1-ene-17-yl]-4-(trifluoromethoxy)phenyl ester 2-37 Carbamicacid, [(5α,17β)-3-oxo-4-methyl- 389.281 azaandrost-1-ene-17-yl]-2-propylester 2-38 Carbamic acid, [(5α,17β)-3-oxo-4-methyl- 389.2847azaandrost-1-ene-17-yl]-1-propyl ester 2-39 Carbamic acid,[(5α,17β)-3-oxo-4-methyl- 403.2998 azaandrost-1-ene-17-yl]-1-butyl ester2-40 Carbamic acid, [(5α,17β)-3-oxo-4-methyl- 431.3301azaandrost-1-ene-17-yl]-1-hexyl ester

EXAMPLE 3 Preparation of4-methyl-17β-(phenylsulfonamido)-4-aza-5α-androst-1-ene-3-one (3-1)

Amine 1-2 (150 mg, 0.497 mmol), diisopropylethylamine (80 μL),phenylsulfonyl chloride (70 μL, 0.550 mmol) and CH₂Cl₂ (3 mL) werecombined and then stirred for 1 hour. The reaction was diluted withCH₂Cl₂ and then washed with 10% aqueous KHSO₄. The organic portion wasseparated, dried over magnesium sulfate, and evaporated. The resultingresidue was purified by flash chromatography (silica, hexanes→EtOAc)providing compound 3-1 (0.100 g, 45% yield) as a yellow solid.

HRMS (FAB, M+1) found 443.2376.

Utilizing the same general procedure as described for compound 3-1 inExample 3, and by varying the sulfonyl chloride reagent, compounds 3-2through 3-13 were prepared (Table 5); mass spectral characterization ofthese compounds is listed in Table 6.

TABLE 5

3-1

3-2

3-3

3-4

3-5

3-6

3-7

3-8

3-9

3-10

3-11

3-12

3-13

TABLE 6 Compound Number Name [M + H]+ Found 3-14-methyl-17β-(phenylsulfonamido)-4-aza-5α-androst- 443.2376 1-ene-3-one3-2 4-methyl-17β-(2-trifluoromethylphenylsulfonamido)-4- 511.2260aza-5α-androst-1-ene-3-one 3-34-methyl-17β-(3-trifluoromethylphenylsulfonamido)-4- 511.2268aza-5α-androst-1-ene-3-one 3-44-methyl-17β-(2-chlorophenylsulfonamido)-4-aza-5α- 477.1990androst-1-ene-3-one 3-54-methyl-17β-(3-chlorophenylsulfonamido)-4-aza-5α- 477.1998androst-1-ene-3-one 3-64-methyl-17β-(2-trifluoromethoxyphenylsulfonamido)- 527.22094-aza-5α-androst-1-ene-3-one 3-74-methyl-17β-(2-cyanophenylsulfonamido)-4-aza-5α- 468.2322androst-1-ene-3-one 3-8 4-methyl-17β-(4-methoxyphenylsulfonamido)-4-aza-473.2492 5α-androst-1-ene-3-one 3-9 4-methyl-17β-(3-bromo-5-- 551.1576methoxyphenylsulfonamido)-4-aza-5α-androst-1- ene-3-one  3-104-methyl-17β-(8-quinolylsulfonamido)-4-aza-5α- 494.2482androst-1-ene-3-one  3-114-methyl-17β-(3-cyanophenylsulfonamido)-4-aza-5α- 468.2299androst-1-ene-3-one  3-124-methyl-17β-(4-chlorophenylsulfonamido)-4-aza-5α- 477.1960androst-1-ene-3-one  3-134-methyl-17β-[(2-methylsufonyl)phenyl]sulfonamido)- 521.21254-aza-5α-androst-1-ene-3-one

EXAMPLE 4 Preparation of N-[(5α17β)-4-methyl-3-oxo-4-azaandrost-1-en-17-yl]-N′-phenyl urea (4-1)

A mixture of 1-2 (1.0 g, 3.31 mmol), diisopropyethylamine (0.09 mL),phenyl isocyanate (0.047 g, 0.41 mmol) and dichloromethane (1 mL) wasstirred for 3 hours. The mixture was washed with 10% w/v aqueouspotassium hydrogen sulfate and the resulting organics chromatographed onsilica gel (0% to 100% ethyl acetate/hexanes) to give 4-1 as a solid.

HRMS (FAB, M+1) found 422.2793.

Utilizing the same general procedure as described for compound 4-1 inExample 4, and by varying the isocyanate reagent, compounds 4-2 through4-17 were prepared (Table 7); mass spectral characterization of thesecompounds is listed in Table 8.

EXAMPLE 4-18 Preparation ofN-[5α,17β)-4-methyl-3-oxo-4-azaandrost-1-en-17-yl]-N′-methyl urea (4-18)

A mixture of 1-1 (1.0 g, 3.02 mmol), diphenylphosphoryl azide (1.0 g,3.62 mmol), triethylamine (0.46 g, 4.53 mmol) and toluene (100 mL) washeated at reflux for 15 hours. After cooling to ambient temperature, themixture was washed with 10% w/v aqueous potassium carbonate and driedover magnesium sulfate. Evaporation of the solvents gave 5-1 (1.0 g,100%) as a yellow solid. A mixture of the crude isocyanate (0.1 g, 0.3mmol), diisopropyethylamine (0.12 mL), methylamine hydrochloride (0.21g, 0.3 mmol) and dichloromethane (1 mL) was stirred for 15 hours. Themixture was washed with 10% w/v aqueous potassium carbonate and driedover magnesium sulfate. Evaporation of the solvents gave a residue whichwas chromatographed on silica gel (0% to 100% ethyl acetate/hexanes) togive 4-18 (0.027 g, 25%) as a solid.

HRMS (FAB, M+1) found 360.2680.

Utilizing the same general procedure as described for compound 4-18 inExamples 4-18, and by varying the amine reagent, compounds 4-19 through4-22 were prepared (Table 7); mass spectral characterization of thesecompounds is listed in Table 8.

TABLE 7

4-1

4-2

4-3

4-4

4-5

4-6

4-7

4-8

4-9

4-10

4-11

4-12

4-13

4-14

4-15

4-16

4-17

4-18

4-19

4-20

4-21

4-22

TABLE 8 Compound Number Name Found [M + H]+ 4-1 N-[(5α,17β)-4-methyl-3-oxo-4-azaandrost-1-en-17-yl]- 422.2793 N′-phenylurea 4-2  N-[(5α,17β)-4-methyl-3-oxo-4-azaandrost-1-en-17-yl]- 490.2669N′-(2-trifluoromethyl)phenyl urea 4-3 N-[(5α,17β)-4-methyl-3-oxo-4-azaandrost-1-en-17-yl]- 490.2665N′-(3-trifluoromethyl)phenyl urea 4-4 N-[(5α,17β)-4-methyl-3-oxo-4-azaandrost-1-en-17-yl]- 456.2409N′-3-chlorophenyl urea 4-5 N-[(5α,17β)-4-methyl-3-oxo-4-azaandrost-1-en-17-yl]- 524.2287N′-(4-chloro-2-trifluoromethylphenyl) urea 4-6 N-[(5α,17β)-4-methyl-3-oxo-4-azaandrost-1-en-17-yl]- 464.2903N′-3-acetylphenyl urea 4-7 N-[(5α,17β)-4-methyl-3-oxo-4-azaandrost-1-en-17-yl]- 486.2512N′-(5-chloro-2-trifluoromethylphenyl) urea 4-8 N-[(5α,17β)-4-methyl-3-oxo-4-azaandrost-1-en-17-yl]- 558.2533N′-(2,4-[bistrifluoromethyl]phenyl) urea 4-9 N-[(5α,17β)-4-methyl-3-oxo-4-azaandrost-1-en-17-yl]- 458.2610N′-(3,4-difluorophenyl) urea 4-10N-[(5α,17β)-4-methyl-3-oxo-4-azaandrost-1-en-17-yl]- 490.2017N′-(2,3-dichlorophenyl) urea 4-11N-[(5α,17β)-4-methyl-3-oxo-4-azaandrost-1-en-17-yl]- 490.2020N′-(2,4-dichlorophenyl) urea 4-12N-[(5α,17β)-4-methyl-3-oxo-4-azaandrost-1-en-17-yl]- 490.2018N′-(3,4-dichlorophenyl) urea 4-13N-[(5α,17β)-4-methyl-3-oxo-4-azaandrost-1-en-17-yl]- 456.2402N′-2-chlorophenyl) urea 4-14N-[(5α,17β)-4-methyl-3-oxo-4-azaandrost-1-en-17-yl]- 524.2298N′-(2-chloro-5-trifluoromethylphenyl) urea 4-15N-[(5α,17β)-4-methyl-3-oxo-4-azaandrost-1-en-17-yl]- 524.2299N′-(4-chloro-3-trifluoromethylphenyl) urea 4-16N-[(5α,17β)-4-methyl-3-oxo-4-azaandrost-1-en-17-yl]- 490.2681N′-(4-trifluoromethyl)phenyl urea 4-17N-[(5α,17β)-4-methyl-3-oxo-4-azaandrost-1-en-17-yl]- 450.3114N′-(2,3-dimethylpheny) urea 4-18N-[(5α,17β)-4-methyl-3-oxo-4-azaandrost-1-en-17-yl]- 360.2680 N′-methylurea 4-19 N-[(5α,17β)-4-methyl-3-oxo-4-azaandrost-1-en-17-yl]- 374.2820N′-ethyl urea 4-20 N-[(5α,17β)-4-methyl-3-oxo-4-azaandrost-1-en-17-yl]-374.2761 N′-dimethyl urea 4-21N-[(5α,17β)-4-methyl-3-oxo-4-azaandrost-1-en-17-yl]- 402.3158 N′-diethylurea 4-22 N-[(5α,17β)-4-methyl-3-oxo-4-azaandrost-1-en-17-yl] 346.2489urea

EXAMPLE 4

Oral Composition

As a specific embodiment of an oral composition of a compound of thisinvention, 50 mg of a compound of the present invention is formattedwith sufficient finely divided lactose to provide a total amount of 580to 590 mg to fill a size 0 hard gelatin capsule.

EXAMPLE 5

Transdermal Patch Formulation Ingredient Amount Compound of formula I 40g Silicone fluid 45 g Colloidal silicone dioxide 2.5 g 

The silicone fluid and compound of structural formula I are mixedtogether and the colloidal silicone dioxide is added to increaseviscosity. The material is then dosed into a subsequently heat sealedpolymeric laminate comprised of the following: polyester release liner,skin contact adhesive composed of silicone or acrylic polymers, acontrol membrane which is a polyolefin (e.g. polyethylene, polyvinylacetate or polyurethane), and an impermeable backing membrane made of apolyester multilaminate. The resulting laminated sheet is then cut into10 cm² patches. For 100 Patches.

EXAMPLE 6

Suppository Ingredient Amount Compound of structural formula I  25 gPolyethylene glycol 1000 1481 g Polyethylene glycol 4000  494 g

The polyethylene glycol 1000 and polyethylene glycol 4000 are mixed andmelted. The compound of structural formula I is mixed into the moltenmixture, poured into molds and allowed to cool. For 1000 suppositories.

EXAMPLE 7

Injectable solution Ingredient Amount compound of structural formula I 5g Buffering agents q.s. Propylene glycol 400 mg Water for injection 600mL

The compound of structural formula I and buffering agents are dissolvedin the propylene glycol at about 50° C. The water for injection is thenadded with stirring and the resulting solution is filtered, filled intoampules, sealed and sterilized by autoclaving. For 1000 Ampules.

EXAMPLE 8

Injectable solution Ingredient Amount Compound of structural formula I 5g Buffering agents q.s. Magnesium sulfate heptahydrate 100 mg Water forinjection 880 mL

The compound of structural formula I, magnesium sulfate heptahydrate andbuffering agents are dissolved in the water for injection with stirring,and the resulting solution is filtered, filled into ampules, sealed andsterilized by autoclaving. For 1000 Ampules.

Following are assays to characterize the activity of the tissueselective androgen receptor modulators of the present invention.

In Vitro and in Vivo Assays for Identification of Compounds with SARMActivity

Hydroxylapatite-Based Radioligand Displacement Assay of CompoundAffinity for Endogenously Expressed AR

Materials:

-   Binding Buffer: TEGM (10 mM Tris-HCl, 1 mM EDTA, 10% glycerol, 1 mM    beta-mercaptoethanol, 10 mM Sodium Molybdate, pH 7.2)-   50% HAP Slurry: Calbiochem Hydroxylapatite, Fast Flow, in 10 mM    Tris, pH 8.0 and 1 mM EDTA.-   Wash Buffer: 40 mM Tris, pH7.5, 100 mM KCl, 1 mM EDTA and 1 mM EGTA.    95% EtOH-   Methyltrienolone, [17a-methyl-³H], (R1881*); NEN NET590-   Methyltrienolone (R1881), NEN NLP005 (dissolve in 95% EtOH)-   Dihydrotestosterone (DHT) [1,2,4,5,6,7-³H(N)] NEN NET453-   Hydroxylapatite Fast Flow; Calbiochem Cat#391947-   Molybdate=Molybdic Acid (Sigma, M1651)    MDA-MB-453 Cell Culture Media:    -   RPMI 1640 (Gibco 11835-055) w/23.8 mM NaHCO₃, 2 mM L-glutamine    -   In 500 mL of complete media Final conc.    -   10 mL (1 M Hepes) 20 mM    -   5 mL (200 mM L-glu) 4 mM    -   0.5 mL (10 mg/mL human insulin) 10 μg/mL in 0.01 N HCl        Calbiochem#407694-S)    -   50 mL BS (Sigma F2442) 10%    -   1 mL (10 mg/mL Gentamicin 20 μg/mL Gibco#15710-072)        Cell Passaging:

Cells (Hall R. E., et al., European Journal of Cancer, Vol. 30A (4),484-490 (1994)) are rinsed twice in PBS, phenol red free Trypsin-EDTA isdiluted in the same PBS 1:10. The cell layers are rinsed with 1×Trypsin, extra Trypsin is poured out, and the cell layers are incubatedat 37° C. for ˜2 min. The flask is tapped and checked to for signs ofcell detachment. Once the cells are starting to sliding off the flask,the complete media is added to kill the trypsin. The cells are countedat this point, then diluted to the appropriate concentration and splitinto flasks or dishes for further culturing (Usually 1:3 to 1:6dilution).

Preparation of MDA-MB453 Cell Lysate

When the MDA cells are 70 to 85% confluent, they are detached asdescribed above, and collected by centrifuging at 1000 g for 10 min at4° C. The cell pellet is washed 2 × with TEGM (10 mM Tris-HCl, 1 mMEDTA, 10% glycerol, 1 mM beta-mercaptoethanol, 10 mM Sodium Molybdate,pH 7.2). After the final wash, the cells are resuspended in TEGM at aconcentration of 10⁷ cells/mL. The cell suspension is snap frozen inliquid N₂ or ethanol dry ice bath and transferred to −80° C. freezer ondry ice. Before setting up the binding assay, the frozen samples areleft on ice-water to just thaw (˜1 hr). Then the samples are centrifugedat 12,500 g to 20,000 g for 30 min at 4° C. The supernatant is used toset-up assay right away. If using 50 μL of supernatant, the testcompound can be prepared in 50 μL of the TEGM buffer.

Procedure for Multiple Compound Screening:

1× TEGM buffer is prepared, and the isotope-containing assay mixture isprepared in the following order: EtOH (2% final Conc. in reaction),³H-R1881 or ³H-DHT (0.5 nM final Conc. in reaction) and 1× TEGM. [eg.For 100 samples, 200 μL (100×2) of EtOH+4.25 μL of 1:10 ³H-R1881stock+2300 μL (100×23) 1× TEGM]. The compound is serially diluted, e.g.,if starting final conc. is 1 μM, and the compound is in 25 μL ofsolution, for duplicate samples, 75 μL of 4×1 μM solution is made and 3μL of 100 μM is added to 72 μL of buffer, and 1:5 serial dilution.

25 μL of ³H-R1881 trace and 25 μL compound solution are first mixedtogether, followed by addition of 50 μL receptor solution. The reactionis gently mixed, spun briefly at about 200 rpm and incubated at 4° C.overnight. 100 μL of 50% HAP slurry is prepared and 100 μL of 50% HAPslurry is added to the incubated reaction which is then vortexed andincubated on ice for 5 to 10 minutes. The reaction mixture is vortexedtwice more to resuspend HAP while incubating reaction. The samples in96-well format are then washed in wash buffer using The FilterMate™Universal Harvester plate washer (Packard). The washing processtransfers HAP pellet containing ligand-bound expressed receptor toUnifilter-96 GF/B filter plate (Packard). The HAP pellet on the filterplate is incubated with 50 μL of MICROSCINT (Packard) scintillint for ½hour before being counted on the TopCount micro scintillation counter(Packard). IC₅₀s are calculated using R1881 as a reference. Tissueselective androgen receptor modulators of the present inventiontypically have IC₅₀ values of 1 micromolar or less.

MMP1 Promoter Suppression, Transient Transfection Assay (TRAMPS)

HepG2 cells are cultured in phenol red free MEM containing 10%charcoal-treated FCS at 37C with 5% CO₂. For transfection, cells areplated at 10,000 cells/well in 96 well white, clear bottom plates.Twenty four hours later, cells are co-transfected with a MMP1promoter-luciferase reporter construct and a rhesus monkey expressionconstruct (50:1 ratio) using FuGENE6 transfection reagent, following theprotocol recommended by manufacture. The MMP1 promoter-luciferasereporter construct is generated by insertion of a human MMP1 promoterfragment (−179/+63) into pGL2 luciferase reporter construct (Promega)and a rhesus monkey AR expression construct is generated in a CMV-Tag2Bexpression vector (Stratagene). Cells are further cultured for 24 hoursand then treated with ligands in the presence of 100 nMphorbol-12-myristate-13-acetate (PMA), used to increase the basalactivity of MMP1 promoter. The ligands are added at this point, at arange of 1000 nM to 0.03 nM, 10 dilutions, at a concentration on 10×,1/10th volume. (example: 10 microliters of ligand at 10× added to 100microliters of media already in the well.) Cells are further culturedfor additional 48 hours. Cells are then washed twice with PBS and lysedby adding 70 μL of Lysis Buffer (1 ×, Promega) to the wells. Theluciferase activity is measured in a 96 well format using a 1450Microbeta Jet (Perkin Elmer) luminometer. AR agonism of tissue selectiveandrogen receptor modulators is presented as suppression of luciferasesignal from the PMA-stimulated control levels EC₅₀ and Emax values arereported. Tissue selective androgen receptor modulators of the presentinvention typically agonize repression typically with submicromolar EC₅₀values and Emax values greater than about 50%.

REFERENCES

-   1. Newberry E P, Willis D, Latifi T, Boudreaux J M, Towler D A.    Fibroblast growth factor receptor signaling activates the human    interstitial collagenase promoter via the bipartite Ets-AP1 element.    Mol Endocrinol. 1997 July; 11(8):1129-44.-   2. Schneikert J, Peterziel H, Defossez P A, Klocker H, Launoit Y,    Cato A C. Androgen receptor-Ets protein interaction is a novel    mechanism for steroid hormone-mediated down-modulation of matrix    metalloproteinase expression. J Biol Chem. 1996 Sep. 27;    271(39):23907-13.    A Mammalian Two-Hybrid Assay for the Ligand-induced Interaction of    N-Terminus and C-Terminus Domains of the Androgen Receptor (Agonist    Mode)

This assay assesses the ability of AR agonists to induce the interactionbetween the N-terminal domain (NTD) and C-terminal domain (CTD) of rhARthat reflects the in vivo virilizing potential mediated by activatedandrogen receptors. (ref. 1). The interaction of NTD and CTD of rhAR isquantified as ligand induced association between a Gal4,DBD-rhARCTDfusion protein and a VP16-rhARNTD fusion protein as a mammaliantwo-hybrid assay in CV-1 monkey kidney cells.

The day before transfection, CV-1 cells are trypsinized and counted, andthen plated at 20,000 cells/well in 96 well plates or larger plates(scaled up accordingly) in DMEM+10% FCS. The next morning, CV-1 cellsare cotransfected with pCBB1 (Gal4DBD-rhARLBD fusion construct expressedunder the SV40 early promoter), pCBB2 (VP16-rhAR NTD fusion constructexpressed under the SV40 early promoter) and pFR (Gal4 responsiveluciferase reporter, Promega) using LIPOFECTAMINE PLUS reagent(GIBCO-BRL) following the procedure recommended by the vendor. Briefly,DNA admixture of 0.05 μg pCBB1, 0.05 μg pCBB2 and 0.1 ug of pFR is mixedin 3.4 uL OPTI-MEM (GIBCO-BRL) is mixed with “PLUS Reagent” (1.6 μL,GIBCO-BRL) and incubated at room temperature (RT) for 15 min to form thepre-complexed DNA.

For each well, 0.4 μL LIPOFECTAMINE Reagent (GIBCO-BRL) is diluted into4.6 μL OPTI-MEM in a second tube and mixed to form the dilutedLIPOFECTAMINE Reagent. The pre-complexed DNA (above) and the dilutedLIPOFECTAMINE Reagent (above) are combined, mixed and incubated for 15min at RT. The medium on the cells is replaced with 40 μL/well OPTI-MEM,and 10 μL DNA-lipid complexes are added to each well. The complexes aremixed into the medium gently and incubate at 37° C. at 5% CO₂ for 5 h.Following incubation, 200 μL/well D-MEM and 13% charcoal-stripped FCS isadded, followed by incubation at 37° C. at 5% CO₂

After 24 hours, the test compounds are added at the desiredconcentration(s) (1 nM-10 μM). Forty eight hours later, luciferaseactivity is measured using LUC-Screen system (TROPIX) following themanufacture's protocol. The assay is conducted directly in the wells bysequential addition of 50 μL each of assay solution 1 followed by assaysolution 2. After incubation for 40 minutes at room temperature,luminescence is directly measured with 2-5 second integration.

Activity of test compounds is calculated as the Emax relative to theactivity obtained by 3 nM R1881. Typical tissue selective androgenreceptor modulators of the present invention display weak or no agonistactivity in this assay with less than 50% agonist activity at 10micromolar.

REFERENCE

-   1. He B, Kemppainen J A, Voegel J J, Gronemeyer H, Wilson E M    Activation function In the human androgen receptor ligand binding    domain mediates inter-domain communication with the NH(2)-terminal    domain. J Biol Chem. V 274: pp 37219-25, 1999.    A Mammalian Two-Hybrid Assay for Inhibition of Interaction between    N-Terminus and C-Terminus Domains of Androgen Receptor (Antagonist    Mode)

The assay assesses the ability of test compounds to antagonize thestimulatory effects of R1881 on the interaction between NTD and CTD ofrhAR in a mammalian two-hybrid assay in CV-1 cells as described above.

Forty eight hours after transfection, CV-1 cells are treated with testcompounds, typically at 10 μM, 3.3 μM, 1 μM, 0.33 μM, 100 nM, 33 nM, 10nM, 3.3 nM and 1 nM final concentrations. After incubation at a 37° C.at 5% CO₂ for 10-30 minutes, an AR agonist methyltrienolone (R1881) isadded to a final concentration of 0.3 nM and incubated at 37° C.Forty-eight hours later, luciferase activity is measured usingLUC-Screen system (TROPIX) following the protocol recommended by themanufacture. The ability of test compounds to antagonize the action ofR1881 is calculated as the relative luminescence compared to the valuewith 0.3 nM R1881 alone.

SARM compounds of the present invention typically display antagonistactivity in the present assay and have IC₅₀ values less than 1micromolar.

In Vivo Prostate Assay

Male Sprague-Dawley rats aged 9-10 weeks, the earliest age of sexualmaturity, are used in prevention mode. The goal is to measure the degreeto which androgen-like compounds delay the rapid deterioration (˜−85%)of the ventral prostate gland and seminal vesicles that occurs during aseven day period after removal of the testes (orchidectomy [ORX]).

Rats are orchidectomized (ORX). Each rat is weighed, then anesthetizedby isoflurane gas that is maintained to effect. A 1.5 cm anteroposteriorincision is made in the scrotum. The right testicle is exteriorized. Thespermatic artery and vas deferens is ligated with 4.0 silk 0.5 cmproximal to the testicle. The testicle is freed by one cut of a smallsurgical scissors distal to the ligation site. The tissue stump isreturned to the scrotum. The same is repeated for the left testicle.When both stumps are returned to the scrotum, the scrotum and overlyingskin are sutured closed with 4.0 silk. For Sham-ORX, all proceduresexcepting ligation and scissors cutting are completed. The rats fullyrecover consciousness and full mobility within 10-15 minutes.

A dose of test compound is administered subcutaneously or orally to therat immediately after the surgical incision is sutured. Treatmentcontinues for an additional six consecutive days.

Necropsy and Endpoints

The rat is first weighed, then anesthetized in a CO₂ chamber until neardeath. Approximately 5 ml whole blood is obtained by cardiac puncture.The rat is then examined for certain signs of death and completeness ofORX. Next, the ventral portion of the prostate gland is located andblunt dissected free in a highly stylized fashion. The ventral prostateis blotted dry for 3-5 seconds and then weighed (VPW). Finally, theseminal vesicle is located and dissected free. The ventral seminalvesicle is blotted dry for 3-5 seconds and then weighed (SVWT).

Primary data for this assay are the weights of the ventral prostate andseminal vesicle. Secondary data include serum LH (luteinizing hormoneand FSH (follicle stimulating hormone), and possible serum markers ofbone formation and virilization. Data are analyzed by ANOVA plus FisherPLSD post-hoc test to identify intergroup differences. The extent towhich test compounds inhibit ORX-induced loss of VPW and SVWT isassessed.

In Vivo Bone Formation Assay

Female Sprague-Dawley rats aged 7-10 months are used in treatment modeto simulate adult human females. The rats have been ovariectomized (OVX)75-180 days previously, to cause bone loss and simulate estrogendeficient, osteopenic adult human females. Pre-treatment with a low doseof a powerful anti-resorptive, alendronate (0.0028 mpk SC, 2×/wk) isbegun on Day 0. On Day 15, treatment with test compound is started. Testcompound treatment occurs on Days 15-31 with necropsy on Day 32. Thegoal is to measure the extent to which androgen-like compounds increasethe amount of bone formation, shown by increased fluorochrome labeling,at the periosteal surface.

In a typical assay, nine groups of seven rats each are studied.

On Days 19 and 29 (fifth and fifteenth days of treatment), a singlesubcutaneous injection of calcein (8 mg/kg) is given to each rat.

Necropsy and Endpoints

The rat is first weighed, then anesthetized in a CO₂ chamber until neardeath. Approximately 5 mL whole blood is obtained by cardiac puncture.The rat is then examined for certain signs of death and completeness ofOVX. First, the uterus is located, blunt dissected free in a highlystylized fashion, blotted dry for 3-5 seconds and then weighed (UW). Theuterus is placed in 10% neutral-buffered formalin. Next, the right legis disarticulated at the hip. The femur and tibia are separated at theknee, substantially defleshed, and then placed in 70% ethanol.

A 1 cm segment of the central right femur, with the femoralproximal-distal midpoint at its center, is placed in a scintillationvial and dehydrated and defatted in graded alcohols and acetone, thenintroduced to solutions with increasing concentrations of methylmethacrylate. It is embedded in a mixture of 90% methyl methacrylate:10%dibutyl phthalate, that is allowed to polymerize over a 48-72 hr period.The bottle is cracked and the plastic block is trimmed into a shape thatconveniently fits the vice-like specimen holder of a Leica 1600 SawMicrotome, with the long axis of the bone prepared for cross-sectioning.Three cross-sections of 85 μm thickness are prepared and mounted onglass slides. One section from each rat that approximates the midpointof the bone is selected and blind-coded. The periosteal surface of eachsection is assessed for total periosteal surface, single fluorochromelabel, double fluorochrome label, and interlabel distance.

Primary data for this assay are the percentage of periosteal surfacebearing double label and the mineral apposition rate (interlabeldistance (μm)/10 d), semi-independent markers of bone formation.Secondary data include uterus weight and histologic features. Tertiaryendpoints may include serum markers of bone formation and virilization.Data are analyzed by ANOVA plus Fisher PLSD post-hoc test to identifyintergroup differences. The extent to which test compounds increase boneformation endpoint will be assessed.

While the foregoing specification teaches the principles of the presentinvention, with examples provided for the purpose of illustration, itwill be understood that the practice of the invention encompasses all ofthe usual variations, adoptions, or modifications, as come within thescope of the following claims and their equivalents.

1. A compound according which is4-methyl-17β-[(4-trifluoromethylphenyl)acetamido-4-aza-5α-androst-1-ene-3-one;or a pharmaceutically acceptable salt thereof.